Frontiers in Topical Photoprotection

Abstract

This review synthesizes the latest research and developments to take into consideration for creating advanced sun protection products that meet evolving consumer demands. It examines the multifaceted effects of solar radiation (UVB, UVA, blue light, and infrared) on the skin, detailing cellular damage mechanisms, including DNA and RNA damage, and oxidative stress. It covers advancements in sunscreen formulation science, delivery systems, and UV filters. It delves into testing methodology advancements addressing in vivo limitations, new regulatory guidelines, and the integration of artificial intelligence from new UV filter development to consumer facing apps. Finally, it highlights biotechnology’s potential to deliver novel sustainable UV filters. By providing a holistic perspective on these interdisciplinary advancements, this review serves as background reading, informing future sunscreen development and fostering a comprehensive approach to photoprotection that address current and emerging challenges.

1. Introduction

Sun protection methods evolved long before commercial sunscreens existed. Across diverse civilizations and continents, people developed methods to shield themselves from the sun that could tan or burn their skin. Ancient Egyptians applied rice bran, jasmine and lupine pastes, while Greeks sought protection in olive oil [1]. Bedouins draped themselves in loose-fitting garments that both reflected sunlight and allowed air circulation (

Table 1. Examples of historically used sun protection methods and materials.

Culture/Period	Sun Protection Method
African Middle Stone Age	Early civilizations used ochre, a pigment from rocks, as sunscreen, adhesive, insect repellent, and leather preservative [4].
Ancient Egyptians (3100–300 BC)	Rice bran, jasmine, and lupine pastes (recently discovered to absorb UV, repair DNA, and lighten skin) [1].
Ancient Greeks (800–500 BC)	Olive oil (modern testing shows SPF ~ 8) [1,5].
Charaka Samhita, a foundational text of Ayurvedic medicine (Indian traditional medicine) (~500 BC)	Pushpanjan (zinc oxide), now a key UV filter, was mainly used to treat wounds and eyes [6].
Japanese (from 700s AD)	Lead- or mercury-based white face powders (o-shiro i), associated with female beauty in Japan [7].
Myanmar (~0 AD)	A paste made from the thanatka tree bark, where marmesin is assumed to serve as a UVA filter [8].
Nomadic Bedouins	Keffiyeh (traditional cotton head covering), loose tunics, henna dye [1].
European nobility (1600s)	Velvet visards (face coverings) and lead-containing whitening cosmetics [7].

) [1]. This intuitive understanding of sun protection isn’t unique to humans. Mammals like hippos, rhinos, and elephants instinctively engage in protective behaviors, coating their skin with mud and dust to create natural barriers against solar radiation [2,3]. These parallel adaptations across species highlight the universal biological challenge posed by intense sun exposure.

The transformation from intuitive folk practices to scientific photoprotection began in earnest during the 19th century, when researchers started systematically investigating the sun’s effects on human skin [7]. The research yielded critical insights: the discovery of ultraviolet (UV) rays, skin pigmentation’s protective role, understanding UV radiation (UVR) as the cause of erythema and skin burns, the establishment of a clear link between sun exposure and skin cancer, as well as the first sunscreens development to protect from UVR [9].

Despite this long history of protective practices and growing scientific understanding, the first commercial sunscreen products did not see the market until the 1930’s. Among the pioneering formulations was “Ambre Solaire Huile”, created by L’Oreal founder Eugène Schueller in 1935 [10]—a product that would help launch a global industry now valued at billions of dollars annually [11].

The evolution from ancient botanical extracts or pigments to today’s sophisticated broad-spectrum formulations mirrors our expanding comprehension of the sun’s complex interactions with human skin. Modern photoprotection stands at the intersection of cell biology, dermatological science, cosmetic chemistry, public health, consumer demands, and environmental sustainability—a multidisciplinary field responding to both ancient challenges and contemporary concerns about increasing UV exposure due to climate change and ozone depletion.

2. The Effects of Sun Exposure on Skin Health

Solar radiation consists of approximately 7% UV, 39% visible, and 54% infrared (IR) radiation [12]. UVR is categorized by wavelength into three groups: UVC (200–290 nm), UVB (290–320 nm), and UVA (320–400 nm), each penetrating the skin at different depths and with the ability to cause damage to living tissue [13]. Radiation penetration properties increase with increasing wavelengths, where UVC, with the shortest wavelengths, has not been the focus of much research as it is stopped by the ozone layer and therefore does not reach the Earth’s surface [14]. UVB wavelengths do reach the earth’s surface but can be significantly reduced by factors such as the stratospheric ozone layer, clouds, solar inclination, geographic latitude, altitude, season, and time of day [15,16]. Due to their enhanced penetration, UVA wavelengths are less affected by these factors and are able to pass through both clouds and window glass [14]. This penetrating ability is particularly pronounced for long UVA wavelengths (UVA1, 340–400 nm) compared to short UVA wavelengths (UVA2, 320–340 nm) [15]. Within the 7% of solar radiation that is UVR, UVA constitutes 95%, while UVB accounts for only 5% [17]. Moreover, UVA1 wavelengths comprise as much as 80% of the total ultraviolet light that reaches the earth [14]. Much research has been conducted to understand the impact of sun exposure and thereby the impact of UVB, UVA2, UVA1, visible (400–780 nm), and IR (780–4000 nm) radiation on the skin. The effects of UVB and UVA1 on the skin have been well studied compared to the impact of UVA2, visible, and IR radiation.

Sun exposure can have both beneficial and harmful effects on skin, determined by exposure time, radiation wavelengths, fluence rates, and individual skin properties [18]. Generally, an immunosuppressive effect can be achieved with low or suberythemogenic doses [19]. Therefore some UV exposure can have beneficial effects on autoimmune diseases (such as psoriasis and vitiligo), diabetes, asthma, and cardiovascular diseases [20]. Moreover, UV exposure is the primary method of boosting serum vitamin D levels, which reduces the risk of cancer, cardiovascular diseases, and other infectious diseases [21].

Different skin phototypes respond uniquely to UVR exposure, with darker skin tones offering more natural protection through increased melanin production, though all skin types remain susceptible to damage [22]. Melanin’s photoprotective properties go beyond UV absorption, it also serves as an antioxidant and radical scavenger [23]. Genetic susceptibility to UVR damage encompasses more factors than skin pigmentation alone. Polymorphisms in genes involved in DNA repair and melanogenesis determine the individual’s UVR sensitivity [24,25,26,27]. These genetic differences combined with factors such as diet, geographical location, and lifestyle contribute to the varying susceptibility of individuals to acute reactions and long-term consequences of sun exposure.

UVR can damage skin through two distinct mechanisms: 1. Cellular components directly absorb UV photons, causing immediate damage. 2. UVR triggers photosensitizing reactions involving either endogenous substances naturally present in the skin or exogenous compounds that have entered the skin. These photosensitizing reactions lead to the production of reactive oxygen species (ROS), including superoxide, singlet oxygen, hydrogen peroxide (H₂O₂), and hydroxyl free radicals, which subsequently damage skin cells and structures [28].

When damaged by UVR, skin cells can activate a UV stress response to preserve genomic integrity through the ribotoxic stress response (RSR), DNA repair mechanisms, and cell cycle checkpoints [29,30]. Additionally, UVR exposure also alters protein-coding gene expression to orchestrate these injury responses [29]. However, failure of this response can lead to immunosuppression, inflammation, photoaging, and cancer development.

Acutely, UVR exposure causes sunburn, which presents as redness, pain, itching, blistering, and wounding [31]. This reaction results from dermal inflammation and epidermal cell death triggered by cytokines and chemokines or immune reactions to cellular contents released by dead cells. The epidermal damage can lead to keratinocyte hyperproliferation, compensating for keratinocyte cell death which can lead to a marked thickening of the epidermis [32].

In terms of chronic effects, exposure to UVR is the primary risk factor for skin cancers and cutaneous melanoma [22]. Both chronic UVB and UVA exposure is associated with melanoma and non-melanoma and skin cancers [33,34,35]. From a photoaging perspective, UVR exposure decreases extracellular matrix components that provide mechanical stability and elasticity, increases advanced glycation end products that impair function, and reduces barrier function through lipid peroxide formation, which increases trans-epidermal water loss [36,37,38].

The skin employs multiple mechanisms to protect itself from damage caused by the sun. Intrinsic antioxidants including glutathione, vitamin C, vitamin E, and antioxidant enzymes including superoxide dismutase and catalase, work alongside chromophores like melanin to protect the skin from oxidative damage [39,40]. Furthermore, repair of DNA can take place via double-stranded break repair, nucleotide excision repair, mismatch repair, and base excision repair [41].

Beyond basic repair pathways, sophisticated molecular signaling networks are involved when damage through UV exposure occurs. The p53 tumor suppressor protein serves as a regulator of diverse cellular processes such as coordinating cell cycle arrest, DNA repair, autophagy, and apoptosis [42]. Despite these natural defense mechanisms, the skin’s protective capacity can be insufficient to mitigate damage from acute or chronic sun exposure [39]. Specifically, when the capacity of the intrinsic antioxidant defense mechanisms are exceeded by the ROS levels, oxidative damage takes place, impacting DNA, proteins, lipids, and other cellular components [43].

2.1. Mechanisms of UVB-Mediated Skin Damage

UVB radiation is generally considered more immediately damaging than UVA due to its higher energy, where the erythema action spectra show that UVB compared to UVA, per unit dose, is orders of magnitude more potent [44,45]. Excess exposure to UVB radiation results in an acute inflammatory reaction of the skin, manifesting as solar erythema [46]. UVB is almost fully absorbed by the epidermis, where melanin pigments, DNA, amino acid chromophores, and prosthetic groups are responsible for the direct absorption of UV photons [47]. UVB penetrates the epidermis and to a lesser extent the dermis, causing multiple damaging effects. It increases carbonylation of epidermal proteins involved in cellular adhesion, mitigating oxidative stress, and protein folding [48]. UVB also induces advanced glycation end product formation in skin keratin, which may alter protein-water interactions and barrier formation [49]. Furthermore, it enhances keratinocyte proliferation [50] and causes DNA damage in keratinocytes, melanocytes, and other skin cells [51].

The damage to DNA is caused by the direct absorption of the radiation energy by pyrimidine bases (cytosine and thymine) [17,18]. This can result in the formation of two types of oxygen-independent DNA modifications: cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6–4) photoproducts (6–4 PPs), which form new bonds between pyrimidine rings [47,52]. These structural alterations to the DNA helix disrupt DNA replication, transcription, and normal base pairing [47]. When damage exceeds critical thresholds, the skin activates mechanisms for DNA repair, cell cycle arrest, and programmed cell death of keratinocytes [47,53].

While countless studies have been performed to understand the effects of UVB exposure to the skin, the underlying molecular mechanisms have still not been fully elucidated.

2.2. UVA Exposure: Cellular Mechanisms and Clinical Outcomes

UVA radiation penetrates significantly deeper into the skin than UVB, reaching well into the dermis and potentially affecting all skin layers from the epidermis to the dermis [14]. Due to the lower energetic properties of UVA radiation, it had long been assumed to have a minimal impact on the skin [54]. This misconception likely persisted partly because UVA produces minimal immediate erythema compared to UVB, creating the illusion of safety. Despite being less energetic than UVB, the penetration capacity of UVA radiation results in photosensitization reactions and ROS generation. When UVA1 photons interact with endogenous chromophores such as porphyrins and flavins, these molecules transfer energy to molecular oxygen, creating singlet oxygen and other ROS that damage cellular structures including proteins such as elastin, collagen and keratin, lipids, and genomic and mitochondrial DNA (mtDNA) [14,55]. UVA-induced ROS can also diffuse to other skin cells causing further damage [56] and can cause carbonylation of proteins, especially in the dermis, presumably due to the lower antioxidant capacity of this skin layer [57,58,59].

While DNA absorption is maximal at 260 nm, UVA can still induce DNA damage. Like UVB, UVA may induce CPDs by direct excitation [60], though due to its weaker direct absorption by DNA the most common mechanism is photosensitization via triplet-triplet energy transfer [61]. This results in “dark CPDs”, occurring after rather than during UV exposure [62]. UVA can also break DNA strands and oxidize bases, with 8-oxo-7,8-dihydroguanine being the most common oxidative lesion and therefore is used as a marker for UVA-induced oxidative damage [63,64]. Furthermore, the oxidative stress caused by UVA1 radiation, can lead to large-scale deletions of mtDNA in human cells, as demonstrated both in vitro and in vivo [65,66,67]. MtDNA is particularly vulnerable due to its lack of histones and limited DNA repair capacity [68], and increased oxidative stress correlates with altered mitochondrial function in vivo [69]. Notably, the ’common deletion’ (4977 bp) is exclusively found in the dermis of photoaged skin [70], indicating UVA1’s significant role in mtDNA mutations. The induction of this deletion is proportional to UVA1 exposure, highlighting the cumulative nature of the photodamage [65]. Consequently, sun-induced mtDNA damage is considered a key factor in the pathogenesis of photoaging.

The clinical outcomes of UVA exposure include tanning, hyperpigmentation, photoaging (wrinkling, laxity, and textural changes), immune suppression, and carcinogenesis [14,71,72].

Lastly, it should be noted that the UVA spectrum itself exhibits heterogeneity in biological effects, with UVA2 and UVA1 demonstrating partially distinct impacts. UVA2, due to its wavelength proximity to UVB, shares some properties with UVB radiation such as erythema [73]. Knowledge on its specific contribution to photoaging is limited, and its biological effects that are distinct from UVA1 and UVB are also not clear. There remains a lack of data on unique molecular effects, damage patterns and its role in photocarcinogenesis.

2.3. Blue Light Effects on Skin: Emerging Mechanisms and Clinical Outcomes

We are exposed to blue light (400–500 nm), through direct exposure to the sun, through atmospheric diffusion, and via reflection off surfaces [74,75]. Significant direct exposure to blue light also occurs through the use of digital devices, light-emitting diodes (LEDs), and fluorescent lighting [74,75]. Recent studies have highlighted visible light’s impact on skin, where blue light over the past years has gained a lot more attention in part due to the increase in use of digital devices that emit it [76]. While the biological effects of UVR have been extensively researched, our understanding of blue light’s impact on human health continues to emerge.

Blue light ranging from violet (400 nm) to turquoise (500 nm) is close to UVA1 in wavelength but penetrates deeper than the dermis, reaching subcutaneous tissue due its longer wavelengths. This penetration has been linked to erythema, hyperpigmentation, and premature aging [77,78,79]. Cell-type, dose, and wavelengths play a role in whether damaging effects such as ROS production are observed [80]. Multiple in vitro studies on human keratinocytes and fibroblasts indicate that harmful effects of blue light such as reduced cell proliferation, DNA damage, and oxidative stress, are observed mainly at <453 nm but less so >453 nm [80,81,82,83]. In vivo, a study on repeat exposure to 450 nm (3 × 60 J cm⁻²) using female volunteers with skin phototypes III and IV demonstrated altered chromophores and triggering of hyperpigmentation [84] indicating that protection from blue light even at >450 nm for individuals with pigmented skin may be beneficial.

At the cellular level, blue light was shown to induce oxidative stress, mitochondrial dysfunction, autophagy blockade, and DNA damage in keratinocytes and melanocytes in vitro [81,82,83]. ROS generated through absorption of photons via chromophores such as porphyrins and flavoproteins appear to be the primary molecular mediator [80,84].

While blue light can damage DNA through oxidation processes involving endogenous chromophores [83], primarily through superoxide anion production [82], this damage is approximately 1000 times less efficient than UVB-induced CPDs [63]. Recent human studies showed dark CPDs were induced at 380 nm but not in the visible range [85], suggesting blue light’s genotoxicity may be more indirect by potentially interfering with repair of UVB damage. One study confirmed, using LED exposure centered at 427 ± 30 nm, that blue light significantly impairs the repair of UV-induced DNA damage in reconstructed human epidermis, reducing the repair rate of CPDs by approximately 50% when samples were exposed to UVB and 25% with a preliminary exposure to blue light [86]. et al. observed formation of pyrimidine dimers in a comet assay in cultured keratinocytes [83]. However, other studies of both cell cultures as well as reconstructed human skin exposed only to blue light did not result in detection of pyrimidine dimers [63,85,87].

A recent study demonstrated changes in composition and conformation of epidermal lipids along with alterations in the structural organization of proteins in a reconstructed human epidermis (RHE) model exposed to 415 nm and 455 nm radiation. While the underlying molecular mechanism for these changes are not yet understood, the study confirms that repeat exposure results in cumulative effects and that wavelengths and exposure doses determine the cellular response [88], as further evidenced by the discrepancies between the publications discussed on blue light and DNA damage.

Skin pigmentation is the clinical outcome of visible light which only has been observed in individuals with skin of color [89]. The pigmentation was found to be both longer lasting and more pronounced compared to pigmentation caused by UVB [90]. The G-protein coupled membrane receptor was found to sense blue light in melanocytes, stimulating melanogenesis through subsequent calcium ion influx [91]. This ultimately led to increase in and clustering of the melanogenesis enzymes tyrosinase and dopachrome tautomerase. The study explained why long lasting pigmentation is observed in skin phototypes III or higher—the clustering of melanogenesis enzymes was mainly observed in dark-skinned melanocytes, inducing sustained tyrosinase activity [91]. Additionally, it was recently found that blue light stimulates pigmentation by activating melanogenesis via CREB/MAPKs and CLU pathways, both in response to calcium influx through activation of TRPV1 after induction of Opsin-3 by blue light, and by inhibition autophagy suppressing melanosome degradation [92].

Beyond skin effects, a new study explored blue light’s impact on hair follicles. Hair follicle stem cells and primary dermal papilla cells (DPC) showed reduced viability and proliferation at 457 nm with intensity dependence. Furthermore, an increased production of ROS was observed in DPCs [93]. If blue light plays a negative role in hair growth or alopecia, and under which conditions, requires further investigation.

Despite its negative effects, which primarily show up as pigmentation in individuals of color, blue light therapy has shown some potential in the treatment of acne [94,95,96,97], psoriasis [98], and alopecia [99].

Sunscreens on the market today are generally not tested for their ability to protect from visible light, nor are there established in vivo methods to assess their efficacy in protecting from blue light. Clear guidelines on potential protection needed from visible light have not yet been established.

While blue light exposure does not appear to be a big risk for most people and a recent study concluded that exposure to digital devices did not result in skin damage [100] more research is needed to understand the long-term impact of consistent blue light exposure from the sun and digital devices such as phones and screens, especially for skin phototypes III or higher.

2.4. Infrared Light: Dual Effects on Skin

IR radiation is divided into IRA (760–1440 nm), IRB (1440–3000 nm), and IRC (3000–10,000 nm) where IRA accounts for about 30% out of the total 54% IR radiation reaching the earth’s surface [101]. When IRA reaches the skin, about half is absorbed in the dermis, with the ability to penetrate all the way to the subcutaneous tissue [102].

IRA from artificial light sources is used for photobiomodulation, a process that employs light to modulate biological processes and cellular functions. The applications range from therapeutic purposes, such as treatment of diabetic skin ulcers, to wellness applications like reduction of wrinkles [103]. The effectiveness of these treatments depend on optimal light parameters—the dose, duration, and specific wavelengths must be carefully selected [104], especially considering that IRA can also contribute to photoaging if the conditions are too aggressive [105,106,107].

At the cellular level, IRA irradiation results in a retrograde signaling response in the mitochondria where generation of ROS induces an increased expression of matrix metalloproteinase-1 (MMP-1) as demonstrated in primary human fibroblasts [108]. Complementing these findings, in vivo studies on human skin have shown that IRA irradiation resulted in upregulation of MMP-1 in the dermis of 80% of the volunteers. Notably, certain antioxidants such as MitoQ (mitochondrially targeted), vitamin C, and epigallocatechin gallate, can mitigate this increase in MMP-1 [106,109].

Further investigating cellular responses, an in vitro study revealed that human fibroblasts treated with multiple doses and repeat exposures with IRA resulted in prolonged cell proliferation, increased ROS production, apoptosis, and elongated cell morphology. The extent of damage however varied between the two dermal fibroblasts tested, derived from a 20-year-old and a 50-year-old woman [110]. Another study has shown that IRA irradiation had a growth inhibiting effect on human epidermal keratinocytes and induced G1 cell cycle arrest, positively correlating with mTORC1 inactivation [111].

Both beneficial and damaging effects of IRA have been demonstrated. Low energy exposure to visible light and IR wavelengths promotes healing benefits in humans, such as accelerated wound healing and reduced skin inflammation, which is why these treatments have been used in dermatological practices for decades [112]. It’s important to note that at least two publications have challenged the in vitro and ex vivo research that has been conducted demonstrating the damaging effects of IRA on humans. One key criticism is that the exposure conditions in many studies do not accurately reflect natural human exposure to IRA from the sun, as the artificial light sources used produced much higher levels than typical solar IRA irradiance thresholds [112,113]. Until this has been appropriately addressed, it may be premature to conclude that sun protection products should be designed to protect against IRA radiation. More research is needed to understand the actual impact of solar IRA exposure on photoaging. However, the use of certain antioxidants to sunscreens or products used before and after sun exposure may be beneficial for protecting from a potential increase in MMP-1 through IRA radiation.

2.5. UV Radiation and Skin Cell Senescence

Exposure of the skin to UVR can induce cellular senescence. Table 2 outlines the various senescence-associated markers that have been cited to be modified by UVR for the most common skin cell types including keratinocytes, fibroblasts, and melanocytes. It should be noted that there are additional markers associated with cell senescence including histone modification (loss of H3K9me3 and H3K27me3 and increasing H3K9ac) [114,115], however this has not yet been elucidated in the context of UV irradiation. UV-induced skin cell senescence can stem from DNA damage, oxidative stress, inflammation, and mitochondrial dysfunction as outlined succinctly in a recent review by Song et al. [116]. UV irradiation can be directly absorbed by DNA resulting in the formation of 6–4 PPs and CPDs or indirectly increase the generation of ROS, leading to oxidation of DNA bases like 8-oxo-guanine [117]. Both direct and indirect DNA damage will lead to apoptosis and cell cycle arrest, and in the context of mtDNA, can disrupt energy generation, all of which are hallmarks of aged cells. The increased generation of ROS can also activate inflammatory pathways like NF-κB and p38MAPK, which contribute to immunosuppression and the accumulation of aging cells, and can also oxidize proteins (ex. protein carbonylation) and lipids (lipid peroxides) that provide structural stability and contribute to metabolic function leading to cellular impairment or destruction [116]. These pathways highlight that UV-induced cellular senescence is not only through a single mechanism, but through a combination of several factors that heavily affect one another. Moreover, it should be noted that cellular senescence can stem from additional extrinsic factors like pollution [118] as well as chronological or intrinsic aging [119,120]. Comparing the relative impact between intrinsic and extrinsic aging, one study found that in aged individuals (61–96 years) in vivo, basal epidermal cells in sun-exposed regions had shorter telomeres in comparison to sun-protected regions [121]. Moreover, in another study, isolated sun-exposed melanocytes expressing senescecent-associated genes showed no changes in relative expression levels as a function of age, nor did melanocytes expressing senescent-associated factors from sun-protected versus sun-exposed biopsies [122]. However, spatial transcriptomics of entire sun-exposed biopsies showed a higher proportion of CDKN1A (a gene which produces the protein p21) spots with a weak association with chronological age. Albeit the sample size in both of these studies were fairly low, 13–15 per group and 2–15 per group, respectively. Further research is necessary to assess the relative contributions of intrinsic and extrinsic aging processes as well as the combination of these factors.

There have been two major strategies published to combat UV-induced cell senescence in skin including preventing senescence through a reduction in oxidative stress and clearing of senescent cells. For example, the use of antioxidants including vitamins and polyphenols have been shown to be effective in reducing photo-induced senescence-associated factors. Pretreatment of keratinocytes [123] as well as 3D epidermal organoids [124] with niacinamide, vitamin B12, before exposure to UVB has been shown to prevent the synthesis of Senescence-Associated Secretory Phenotype (SASP) factors and to restore lamin B1 levels. Doxercalciferol, a vitamin D2 analog, has also been shown to reduce UVB induced SASP factors, as well as SA-β-Gal-positive cells, p16, p21, and p53 in both keratinocytes and mice [125]. Moreover, there has been a plethora of studies looking at polyphenols such as luteolin [126], salvionic acid B [127], hydroxytyrosol [128], salidroside [129], apigenin [130], and shikimic acid [131] in their ability to prevent UV-induced modifications in senescence associated factors in vitro. In most cases the mechanism of action for these antioxidants is through modification of oxidative stress pathways to prevent or mitigate the formation of ROS and subsequent cytokine signaling. Another strategy for combating photo-induced cell senescence is the selective clearing of senescent cells using senolytic drugs. Kim et al. identified two senolytic synthetic peptides, ABT-737 and ABT-263, that selectively decreased the viability of UV-induced senescent melanocytes [132] and dermal fibroblast [133], but not normal young respective cells, which was also confirmed effective with UV-irradiated mouse skin as well [134].

Table 2. Outline of UV modified senescence-associated markers.

Marker	Function	Cell Types	UV Effect	Refs.
SA-β-gal	accumulates in the lysosomes of senescent cells.	Keratinocyte Fibroblast Melanocyte	↑	[120,131,135,136]
p16	tumor suppressor, which induces cell-cycle arrest and senescence	Keratinocyte Fibroblast Melanocyte	↑	[120,131,135,137,138]
p21	cyclin-dependent kinase inhibitor, inhibits cell proliferation	Keratinocyte Fibroblast Melanocyte	↑	[135,137,139]
p53	tumor suppressor, frequently mutated in skin cancer cells	Keratinocyte Fibroblast Melanocyte	↑	[135,140,141,142]
Lamin B1	ensures the stability of nuclear structure and regulates chromatin distribution, DNA replication and transcription, gene expression, and cell cycle maintenance.	Keratinocyte Fibroblast Melanocyte	↓	[136,139,143]
Telomere-associated foci (TAFs)	structures that form at the ends of telomeres when they become damaged or dysfunctional	Melanocyte	↑	[120]
mtDNA mutations	mutations result in mitochondrial dysfunction, which can manifest as disruption of energy production and exacerbation of ROS production [144,145]	Keratinocyte Fibroblast Melanocyte	↑	[144,145]
DNA methylation (DNMT1)	epigenetic marker involved in activating the X chromosome, silencing repetitive elements of the genome, inhibiting gene transcription and genomic imprinting	Keratinocyte Fibroblast	↑	[146,147]
Senescence-Associated Secretory Phenotype (SASP) factors	a collection of soluble signaling factors including cytokines, chemokines, and growth factors, secreted proteases, and secreted insoluble proteins/extracellular matrix components (ECM)	Keratinocyte Fibroblast Melanocyte	↑	[123,148,149,150,151]
mTOR	protein kinase complex that integrates mitogenic signals to synthesize growth factors and ATP to drive anabolic pathways such as protein translation, lipid and nucleotide biosynthesis and organelle biogenesis	Keratinocyte Fibroblast	↑	[152,153]
HMGB1	nuclear protein that is involved in transcriptional activation, DNA folding, and tissue damage signaling. In senescent cells, HMGB1 translocates from the nucleus to the cytoplasm and extracellular space, facilitating the release of SASP factors	Keratinocyte Melanocyte	↑	[154,155,156]
SIRT1	NAD+-dependent deacetylase that regulate cellular stress response through DNA repair, chromatin regulation, metabolism, and inflammation.	Keratinocyte Fibroblast	↓	[157,158]

The arrow up means that expression of the marker upon UV exposure has increased and the arrow down means expression of the market upon UV exposure has decreased.

Table 2. Outline of UV modified senescence-associated markers.

Marker	Function	Cell Types	UV Effect	Refs.
SA-β-gal	accumulates in the lysosomes of senescent cells.	Keratinocyte Fibroblast Melanocyte	↑	[120,131,135,136]
p16	tumor suppressor, which induces cell-cycle arrest and senescence	Keratinocyte Fibroblast Melanocyte	↑	[120,131,135,137,138]
p21	cyclin-dependent kinase inhibitor, inhibits cell proliferation	Keratinocyte Fibroblast Melanocyte	↑	[135,137,139]
p53	tumor suppressor, frequently mutated in skin cancer cells	Keratinocyte Fibroblast Melanocyte	↑	[135,140,141,142]
Lamin B1	ensures the stability of nuclear structure and regulates chromatin distribution, DNA replication and transcription, gene expression, and cell cycle maintenance.	Keratinocyte Fibroblast Melanocyte	↓	[136,139,143]
Telomere-associated foci (TAFs)	structures that form at the ends of telomeres when they become damaged or dysfunctional	Melanocyte	↑	[120]
mtDNA mutations	mutations result in mitochondrial dysfunction, which can manifest as disruption of energy production and exacerbation of ROS production [144,145]	Keratinocyte Fibroblast Melanocyte	↑	[144,145]
DNA methylation (DNMT1)	epigenetic marker involved in activating the X chromosome, silencing repetitive elements of the genome, inhibiting gene transcription and genomic imprinting	Keratinocyte Fibroblast	↑	[146,147]
Senescence-Associated Secretory Phenotype (SASP) factors	a collection of soluble signaling factors including cytokines, chemokines, and growth factors, secreted proteases, and secreted insoluble proteins/extracellular matrix components (ECM)	Keratinocyte Fibroblast Melanocyte	↑	[123,148,149,150,151]
mTOR	protein kinase complex that integrates mitogenic signals to synthesize growth factors and ATP to drive anabolic pathways such as protein translation, lipid and nucleotide biosynthesis and organelle biogenesis	Keratinocyte Fibroblast	↑	[152,153]
HMGB1	nuclear protein that is involved in transcriptional activation, DNA folding, and tissue damage signaling. In senescent cells, HMGB1 translocates from the nucleus to the cytoplasm and extracellular space, facilitating the release of SASP factors	Keratinocyte Melanocyte	↑	[154,155,156]
SIRT1	NAD+-dependent deacetylase that regulate cellular stress response through DNA repair, chromatin regulation, metabolism, and inflammation.	Keratinocyte Fibroblast	↓	[157,158]

The arrow up means that expression of the marker upon UV exposure has increased and the arrow down means expression of the market upon UV exposure has decreased.

2.6. UV Radiation Effects on RNA

UVR not only has the ability to damage DNA but also RNA. There is now an understanding that the skin’s immediate response to UVB radiation resulting in solar erythema, or sunburn, is triggered by RNA damage [30,159]. Keratinocytes rely on a cytoplasmic and ribosomal stress signal for rapid inflammatory responses to UV exposure [30,159]. Upon UVB exposure, in keratinocytes, mRNA nucleotides crosslink which causes stalling and subsequent collision of ribosomes on the mRNA templates [160,161], this activates the RSR as well as zipper sterile-α-motif kinase (ZAK) signaling [30]. ZAKα is a stress-associated mitogen-activated protein kinase that is activated by a range of cellular stress insults, including UV irradiation. Following the activation of ZAKα, RSR signaling leads to both p38-mediated pyroptotic cell death and JNK-mediated apoptotic cell death. Additionally, the RSR signaling elicits p38 and MK2-dependent secretion of inflammatory cytokines and chemokines [159]. Notably, when researchers used ZAK knockout mice, they observed significant protection against UVB-induced skin inflammation, keratinocyte death, and subsequent epidermal thickening [159].

Beyond the immediate response to UVB radiation, UV-damaged RNA also plays a critical role in determining the fate and functionality of daughter cells. As cells divide, daughter cells receive more than just genetic material from their parent cells—they also inherit non-genetic components. Research across yeast, Drosophila melanogaster, and mammalian species has shown that the transmission of mRNA molecules from mother to daughter cells significantly influences the fate of the daughter cells [162,163,164,165]. A specialized stress granule marked by the double-stranded RNA helicase DHX9 has been identified that specifically contains UV-damaged RNA, but not damaged DNA [166]. Unlike traditional stress granules that contain mature mRNA, these DHX9 stress granules are rich in damaged intron RNA. UV exposure causes RNA crosslinking damage, interferes with intron splicing and decay, and triggers these DHX9 stress granules to form in daughter cells [166]. These specialized stress granules help cells survive by triggering immune responses to double-stranded RNA and shutting down translation, which differs from classical stress granules that form downstream translation arrest. The autophagy receptor p62 plays an important role in breaking down these stress granules [166].

These findings highlight the complex and multifaceted role of RNA damage in UV-induced skin responses and may contribute to advancing the development of treatments for chronic skin diseases that are aggravated by sun exposure.

2.7. The Circadian Rhythms Impact on UV Damage Severity

The circadian rhythm regulates both our sleep-awake rhythm as well as biological timekeeping of many cellular processes aligned with the 24 h light-dark cycle of the earth [167]. The skin is also under circadian control and newer research points to the importance of circadian rhythms in modulating UVB damage susceptibility [168,169]. The expression and activity of key DNA repair enzymes fluctuate throughout the day, controlled by the circadian clock machinery [170]. Studies in both mouse models and human skin explants demonstrate that identical UVB doses administered at different times of day produce varying levels of DNA damage and mutation risk [18]. In one study with 20 volunteers exposed both in the morning and evening to four-fold standard erythema doses of UVB irradiation (309–313 nm) demonstrated differences in gene expression both between morning and evening exposure as well as compared to the unexposed control. While proinflammatory M1 macrophages were increased at both timepoints, the erythema was more severe and more strongly correlated with the evening timepoint [18]. As a result of a study on human keratinocytes the authors suggest there may be a UVB regulated system in human skin that independently operates as a timekeeping system [171]. More research is needed to confirm such findings. The considerations of the circadian rhythm may especially be of importance to individuals that have a disrupted circadian rhythm through working night shifts or individuals receiving phototherapy for skin diseases, where the skin may be able to better protect itself from damage in exposure during the day vs. exposure in the evening.

2.8. Comparative Effects of Acute and Chronic UVR Exposure

Chronically irradiated (>1 dose) or sun-exposed skin can sometimes be as simple as a more accentuated accumulation of the acute instances of irradiation, but in other biomarkers, the chronically irradiated skin can take on a different effect. For example, structural proteins such as collagen [172,173], elastin [174] and laminin [175,176] that undergo acute UV irradiation of non-sun exposed skin have shown to produce similar alterations in protein levels compared to sun-exposed skin (under chronic exposure to UV irradiation). Alternatively, proliferation and apoptosis are affected differently when it comes to acute and chronic irradiation. Ouhtit et al., show that keratinocytes in mice exposed to acute irradiation that generate DNA damage are able to be eliminated by apoptosis, facilitated in part by high levels of Fas and Fas-L interactions [177]. Contrastingly, upon chronic UV irradiation, there is a loss of Fas-L expression and a gain in p53 mutations, an important regulator in DNA repair, leading to dysregulation of apoptosis, expansion of mutated keratinocytes, visually observed in the form of epidermal hyperplasia [178,179], and initiation of skin cancer. In support, Mitchel et al. showed that chronic irradiation of skin has a significantly slower 6–4 PPs DNA repair time and extent compared to acute irradiation of skin [180]. As for dermal fibroblasts, for both human and mice, acute UV irradiation led to an increase in DNA damaged fibroblasts and drop in papillary fibroblast cell density within the first few days post-irradiation, followed immediately by a surge in proliferation, increased motility, and a restoration in tissue density over the course of the remaining 14 days of observation [181]. Opposingly, chronic UV irradiation prevented repopulation of papillary fibroblasts in the upper dermis even after 30 days post irradiation. This reduction in cell density with prolonged irradiation exposure seems to be in line with other studies [182] and is suggested to be associated with premature skin aging, reduction in regeneration, and a profibrotic environment [183,184,185,186].

The skin’s immune response to chronic versus acute irradiation also has a juxtaposition effect. The activation of inflammatory pathways with acute irradiation effects on the skin are well understood and characterized by an increased release of proinflammatory cytokines and matrix metalloproteinases [187,188]. Irradiation can damage and modify DNA, lipids and proteins directly or indirectly through the generation of ROS. This cellular stress can trigger an inflammatory response in both immune and non-immune cells, most notably through NF-κB and p38MAPK pathways [116]. Alternatively, chronic irradiation can contribute to immunosuppression.

In the pathogenesis of immunosuppression, a constant flurry of acute irradiation-induced inflammation, subsequently triggers the stimulation and recruitment of immunosuppressive cells within the skin to combat the inflammation, namely regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), regulatory B cells (Bregs), and regulatory dendritic cells (DCregs) [188]. When these cells reach the site of inflammation, they can release anti-inflammatory cytokines such as IL-10 and TGF-β; release ROS compounds, reactive nitrogen species, and Prostaglandin E2 (PGE2); and change the expression of amino acid metabolizing enzymes [188]. The release of these immunosuppressors can promote the senescence of cells in the skin, which does not only impair their function, but also express a pro-inflammatory SASP, which in turn, further contributes to the chronic inflammation and subsequent cyclic activation of immunosuppressive cells, disrupting skin homeostasis and contributing to the photoaging process [188].

2.9. Beyond UV Radiation: Combined Environmental Impacts

While many studies have looked at the effects of UV irradiation on the skin, UV is only one of many environmental stressors the skin is exposed to. These additional stressors include visible and infrared radiation, ozone, particulate matter, humidity, and temperature [189]. Some studies have already shown that in combination with UVR, these environmental stressors can create a synergistic negative effect on the skin. For example, an additive effect on cutaneous inflammatory markers and membrane barrier proteins were seen as a consequence of skin oxidative damage upon exposure to UV irradiation in combination with ozone and diesel engine exhaust [190]. This increased damaging effect has been observed independently with ozone in combination with UV irradiation [191] as well as particulate matter with UV irradiation [192,193]. The authors postulate that all 3 stressors are known to induce oxidative stress, but the mechanism of action is different for each. For example, ozone, while not being able to penetrate the skin, is able to interact with surface level lipids including squalene and polyunsaturated fatty acids, leading to the generation of lipid peroxides [194]. Particulate matter derived from diesel engine exhaust has similarly been shown to induce surface level lipid peroxides and is not thought to be able to penetrate healthy skin [195,196]. However ultrafine particles within particulate matter can penetrate damaged stratum corneum [197,198]. Polycyclic aromatic hydrocarbons within particulate matter can also absorb UVA light and become photosensitized through the transfer of one electron to molecular oxygen to form ROS or react with other molecules to generate reactive intermediates [199]. In contrast, UVB can penetrate the epidermis, while UVA can penetrate the epidermis and dermis, both of which can induce, directly or indirectly, the production of ROS [200] as discussed in previous sections. The synergistic oxidative stress effect observed with the combination of UV irradiation with ozone and diesel engine exhaust could as suggested by the authors therefore be due to the decrease in barrier function, which makes the skin more accessible to other stressors that do not permeate as well to cause more damage [190].

There have been only a few studies looking at the combined effects of temperature and UV irradiation [201,202], while none on the combined effects of humidity and UV irradiation. In vitro, a study has shown that elevated temperatures with UV irradiation has an additive effect on ROS and MMP1 production in dermal fibroblasts [201]. In vivo, exposure to elevated temperatures before UV irradiation can actually show a delayed tumor onset and contain fewer skin tumors compared to UV only or UV with heat in hairless mice [202]. In the context of the contribution of other solar wavelength regions on UV induced skin damage, Hudson et al. showed that, while visible light and infrared both individually and in combination did not increase the generation of ROS in both primary keratinocytes and fibroblast, inclusion of both regions with UV synergistically increased oxidative stress compared to UV alone for primary fibroblasts only. While UV alone did increase ROS for primary keratinocytes, the addition of the other regions did not have a significant effect [203].

2.10. Internal Photoprotection: The Gut-Skin Axis

As early as 1953, there have been studies to look at the effects of oral supplementation for UV protection [204]. Most studies since then have looked at carotenoids (ex. lycopene, β-carotene, lutein) [205,206,207,208,209,210,211,212], polyphenols (ex. flavonoids, catechin) [213,214,215,216,217,218], vitamins [208,219,220,221], Polypodium leucotomos [222,223,224,225,226,227,228], and probiotics [229,230,231] with endpoint measurements chiefly inflammation (ex. erythema, PGE2, immune cell infiltration) [209,211,212,213,214,215,216,223,224,225,226,231], oxidative stress markers (ex. MDA, HO1, FRAP) [206,208,217,219], dermal extracellular proteins (ex. collagen, fibrillin, MMP1) [210,213,214,218,223,230] and DNA damage (ex. thymine dimers, p53) [220,221,222,224,225]. A commonality between these ingredients is their association with high levels of antioxidant activity, which is thought to contribute to these observed therapeutic and preventative effects against photodamage [232]. There are some advantages to utilizing an oral route of delivery, including avoiding the need to traverse the hydrophobic stratum corneum barrier [233] and, by utilizing the bloodstream, a more even distribution of active ingredient across the body can be achieved [232]. While this research has been done in vivo on mice and humans, there have been recent efforts to recapitulate the gut-skin processing of these ingredients through in vitro and ex vivo models to better understand the pharmacokinetics of metabolism and delivery, which is quite scarce in the literature [217,232,234]. For example, co-culturing of intestinal epithelial cells (Caco-2) on transwells above epidermal cells (HaCat) as well as the culturing of epidermal cells in intestinal epithelial conditioned media directly have been methods used to study the metabolism and subsequent enhanced barrier function effects of both hyaluronic acid with Bifidobacterium postbiotic [235] as well as paramylon extracted from Euglena gracilis [236]. In the context of photoprotection, Ivarsson et al. developed a model that used endothelial cells to mimic metabolization of wild blueberries in the gut, which they then co-cultured with ex vivo skin biopsies placed in transwell inserts [237]. After UV irradiation of the skin biopsies, they found a reduction in photodamage induced lipid peroxidation and proinflammatory enzymes and cytokines compared to endothelial cells that did not receive blueberries [237]. Similar protective effects were shown in vivo in mice, including reducing inflammation as well as oxidative stress with topical application of a polyphenol-enriched blueberry preparation before UV irradiation [238]. Additionally orally administered blueberry was shown to reduce UV-induced oxidative stress, however the supplement also contained black rice (7:3 blueberry to black rice) and fermented by Lactobacillus plantarum [239].

More direct translation research of ingredients impact on the ex vivo models and how they compare in vivo are needed to validate their use. The use of oral supplementation does not act as a substitute for UV filters, which provide direct sun protection, but rather as a complimentary measure to support additional resilience against oxidative stress and inflammation [240].

2.11. Skin Microbiome Dynamics Under UV Exposure

The skin microbiome, a complex ecosystem of bacteria, archaea, fungi, phages, viruses, and other genetic material, plays a critical role in maintaining skin barrier function, immunity and overall skin health [241,242,243]. Understanding the interplay between solar radiation and this microbial community remains an emerging field of research, with potential implications for skin health and protection strategies.

UVR has been shown to influence the skin microbiome composition, diversity and metabolome [244,245]. UVR exposure has also been shown to reduce the abundance of beneficial bacteria, such as Staphylococcus epidermidis, one of the most abundant skin commensals that produces antimicrobial peptides protecting against pathogens and supporting skin barrier function [246,247]. Harel et al. demonstrated that certain skin microbiome bacterial genera reported to have UV protecting properties, in particular Sphingomonas and Erythrobacteraceae, were enriched following sun exposure [248].

In an in vitro study exposing individually cultured skin commensals to UVB radiation, delayed bacterial growth in several strains of Staphylococcus aureus, S. epidermidis, and Staphylococcus hominis was observed [249]. However, some strains of Micrococcus luteus and Corynebacterium striatum demonstrated resistance to UVB exposure. Even within species, the response varied, as demonstrated by S. epidermidis, where one out of three subspecies tested was unresponsive to UVB radiation [249]. The survival rates of microorganisms upon UV exposure generally depend on the method [249,250], dose, intensity, and exposure time selected and therefore needs to be taken into consideration when independent in vitro results are evaluated or compared. While important to characterize the individual microorganisms response to UVR, these in vitro methods do not reflect the complex reality of the skin environment where microorganisms exist within diverse ecosystems that vary in environment (moist, dry, sebaceous) and therefore vary in microbiome composition [251] Nor are the UV exposure conditions equivalent to natural solar radiation making it difficult to translate to real world applications.

There are indications that the skin microbiome contributes to protect the skin from UVR damage. A study on mice found diminished UV-induced systemic immune suppression in mice with a microbiome compared to those without. The skin microbiome reduced the immunorepressive response to UV irradiation by modulating gene expression and cellular microenvironment of the skin [252]. Additionally, certain microbiome-derived metabolites, such as short-chain fatty acids, can modulate the skin’s immune response to UVR-induced damage, offering a protective effect [244].

The skin microbiome also appears to play a key role in the severity of polymorphic light eruption (PLE), the most common photodermatosis in Europe. Individuals with this disease experience itching or burning lesions upon sun exposure [253]. Human volunteers with and without PLE were exposed to UV irradiation and an increase in the bacterial abundance and Staphylococci was observed. Moreover, the bacterial diversity of volunteers with PLE was reduced both before but even more so after UVR exposure compared to healthy volunteers [249]. Within one week after exposure, the skin microbiomes of volunteers however returned to pre-exposure, speaking to the resilience of the skin microbiome, as also demonstrated in a number of other studies [249,254,255]. Prior research has already suggested that the skin microbiome plays a role in regulating cytokines in response to UV exposure, indicating that skin microorganisms may be involved in the immune response characteristic of PLE [256].

Further research, with larger cohorts and realistic sun exposures is needed to fully understand the sun’s impact on the skin microbiome and to elucidate the variables contributing to discrepancies in research regarding the impact of UV exposure on the skin microbiome [250,257]. For instance, one recent study applying both sunscreen and a placebo (containing no UV filters) to human volunteers and exposing skin to 2 minimal erythema doses (MED) found no significant changes to the skin microbiome [250], unlike some earlier findings.

Understanding the complex relationship between the skin, the skin microbiome, and solar radiation opens new avenues for developing sun protection products, products to prevent photoaging, and therapeutics for some skin diseases. Further research is required to expand on knowledge on the effects of solar radiation to the skin microbiome and what role the skin microbiome may play in skin health upon sun exposure. This will determine the relevance of developing sunscreens that protect or otherwise consider the skin microbiome.

3. Advances in Formulating Sunscreens

The expanding knowledge of the solar spectrum’s biological effects and consumer demands has driven significant advances in photoprotection strategies [258]. Modern sun protection must address a complex array of challenges: defending against multiple wavelengths of radiation, maintaining photostability, ensuring even coverage, and meeting consumer demands for aesthetically pleasing formulations.

The American Academy of Dermatology recommends daily use of broad-spectrum sunscreen with a Sun Protection Factor (SPF) of 30 or higher [259]. While skin sun protection is important to safeguard against photoaging, (hyper)pigmentation, solar erythema, and cancer, there is still an inconsistent or lack of use of sun protection due to factors such as limited education, cost, gender, age, and skin phototype [260,261,262,263,264]. The cost of sunscreens has been reported to be a barrier for its use especially among low-income individuals [260] and among those on with higher skin pigmentation, there is a significant level of inconsistent or no use of sunscreen compared to less pigmented skin types that burn more easily [261]. Prevention of sunburn is one of the key reasons people purchase and apply sunscreen and while skin cancer has a higher occurrence in Caucasians, it is often identified in the later stages and is associated with higher mortality in people of color [260,265]. Practitioners and dermatologists should take level of education, cost, gender, age, and skin phototype into account in their education and recommendations of sunscreens to patients. Formulation chemists, product developers, and brands should also be mindful of these factors when developing and marketing suncare products.

Sunscreen Formulation and Delivery Optimization

The formulation chassis of a sunscreen is critical to the stability and efficacy of the product. Generally, formulation development consists of four steps including the final product design, choice of active UV filters, formulation vehicle, and finally optimization [266]. Sunscreens can be designed for many applications such as lotions, gels, sprays, ointments, and sticks [267]. When designing a sunscreen formulation, some of the most critical characteristics for product success include spreadability, viscosity, particle size of the filters, water resistance, and aesthetic appeal [266]. The user experience is paramount to product success because the formula must satisfy all aesthetically desired properties for consumers to consistently apply enough product such that they are achieving the maximum SPF as specified on the label [267,268].

Sensory analysis performed by Vollhardt et al. indicates that the most desired properties during the rub-out of sunscreen formulas include wetness, high spreadability, low thickness, low whiteness, low oiliness, and fast absorbency [269]. After the product dries down, the key properties include low gloss, minimal whiteness, low stickiness, high slipperiness, low residue, and low greasiness often described as dry touch [269]. Regardless of the characteristics before or after spreading, the results are consequences of how a formulation interacts with the skin and more importantly, the stratum corneum. Upon contact with the skin, the hydrolipidic film is the first substrate that interacts with any dermal formulation. Like any surface, the skin too possesses physico-chemical parameters like surface energy and contact angle [270]. The parameter that becomes crucial to formulators is the critical surface tension of skin. Khyat et al. investigated this and found that the presence or absence of lipids on the skin surface is a critical factor on skin wettability, and concluded that addition of lipids that are similar to the inherent sebaceous lipids increase the wettability of skin [271]. The experiment was carried out by applying both oil in water (O/W) and water in oil (W/O) emulsions, indicating that interaction between the sebaceous layer and the oil phase of the emulsions takes place irrespective of the external or internal phase of emulsions. This was shown again by Hashizaki et al. when devising a method to measure the surface energy of topical formulations [272]. The formulations are spread thin on a glass slide (12 um) using a draw down bar and the contact angle of liquids of varying polarity and hydrophilicity are placed on the prepared slide. When conducting the experiment with water and diiodomethane (DIM) on a slide coated with a W/O emulsion, the contact angle of both water and DIM on the W/O emulsion changes after contact with the emulsion [272]. Both hydrophilic and hydrophobic liquids interact with the external and internal phases of the emulsion. The above results point to an avenue of optimization of spreading by study of physicochemical interactions of the hydrolipid stratum corneum film with any sunscreen formulation. A higher reduction in the surface energy of skin after application of a sunscreen formulation makes the skin more wettable to the formulation and the formulation more spreadable.

Formulation development of a sunscreen emulsion is done with the goal of achieving efficient application of the formulation and thus deposition of the UV absorbers onto the skin. Optimizing spreading characteristics on a uniform substrate like glass which is dissimilar to a complex non-uniform substrate like skin, creates a very common phenomenon where the in vitro performance of a formulation is not representative of the in vivo performance on human skin [273]. Eudier et al. present a survey of all marketed skin models suitable for spreading but delve into detail on two substrates: VitroSkin(™) from Florida Suncare Inc., and BIODY plates by Beaulax. The former best represents skin polarity and pH whereas the latter best represents skin texture. The authors also illustrate that studying films on skin models would help in simulating the tactile properties of interest after application of a formulation [270].

The formulation chassis that most comply with consumer’s desired properties are emulsions. O/W emulsions tend to be preferred for ease of spreading, faster dry-down, and less greasy after-feel, while W/O emulsions can provide greater moisturization and more inherent water resistance [267,274]. Water resistance is important for lasting UV protection due to both submersion (water activities) and sweat production. Emulsions can achieve water resistance primarily in W/O formulations, where the water evaporates or is absorbed into the skin and the oil phase and emulsifier are homogeneously dispersed on the skin such that water cannot be incorporated back into the interface. Water resistance can also be achieved in O/W formulations that contain minimal emulsifiers along with film forming polymers [268].

Apart from aesthetics and water resistance, both emulsion types have pros and cons for sunscreen performance, which primarily depends on the film thickness distribution of the formula [275]. Multiple studies in the literature agree that different sunscreen chassis containing the same UV filter composition will produce varying results of both SPF values in vivo and UV absorption in vitro [276,277,278]. This is due in part to which phase of the emulsion the UV filters are distributed within, and whether there are UV filters in one or both phases. In an O/W emulsion, both inorganic and organic UV filters are distributed in the internal phase droplets which must release and merge upon application and form a uniform film on the skin. After the water phase evaporates, the nonvolatile components will remain, and if they do not have UV filtration capacity, this creates unprotected spots along the film that reduce overall performance [276].

These variations in sunscreen performance can be addressed by optimizing formulation vehicles to achieve homogeneous and uniform distribution of UV filters during application and upon dry-down on the substrate. In the case of mineral filters, waxes can be used to build viscosity and optimize the emulsion stability for film formation by preventing agglomeration into the skin furrows [276]. Zinc oxide and titanium dioxide may also be utilized in coated formats. Organic coatings can improve ease of formulation in either water or oil phases and reduce surface activity [274]. Substances such as silica, alumina, stearic acid, or silicones are also used to coat the minerals to further prevent agglomeration, maintain dispersion, and improve stability of the UV filters [268]. In addition to improved aesthetics, multifunctional coatings are also available where the minerals are surface-treated with antioxidants or free radical quenchers to impart a biological benefit to the skin and even increase SPF in vivo [279].

There are also disadvantages and challenges that come with formulating products with inorganic UV filters. Dispersion difficulties of these filters can lead to unfavorable aesthetics in formulation, specifically the white cast on the skin [280]. This has been addressed with the use of nanoparticles, usually coated and pre-dispersed, which are nearly invisible on the skin. However, as the particle size decreases, the absorption also decreases and shifts to the UVB region. This may boost a higher SPF, but not broad-spectrum coverage. Additionally, zinc oxide when untreated can release hydroxide ions that can increase the pH of sunscreen formulations, leading to emulsion instability [268].

Conventional sunscreen formulations include molecules or particles of UV absorbing actives either dissolved or dispersed in a compatible solvent often accompanied by stabilizer compounds that help maintain the state of dissolution or dispersion as formed at the time of manufacture throughout the shelf life [281,282]. Evaporation, isomerization, fragmentation, reactivity with other molecules, free radical oxidation and UV-induced photo-instability can cause degradation of the UV absorbing molecules or specific UV chromophore within the molecule [281,282]. Drug delivery methodologies based on encapsulation of UV filters have been researched over the last decade as a means of preventing or slowing down UV filter degradation. Nanoemulsions formed with susceptible UV filters like avobenzone and octinoxate, emulsifiers and a solid wax through high speed homogenization have been shown to both stabilize the UV absorption activity and also increase the SPF of the formulation anywhere from 50% to 150% [283].

Liposomes can also be used to encapsulate both oil soluble and aqueous UV filter molecules, and remain a popular method to process and prepare UV filters for formulation [284]. Liposomes are bilayered capsules made from phospholipids and sterols and resemble the cell bilayer and chemical makeup of the stratum corneum. They can thus be included in productions for sensitive skin that do not elicit an allergic reaction. However, this advantage must be weighed against the permeability that comes with liposomal encapsulation of the UV filters [284]. Monteiro et al. introduced modifications to liposomal encapsulation by using it in conjunction with additional encapsulation methodologies including beta cyclodextrins and reportedly arrested the permeability of the UV filters to the epidermis [285]. Nanostructured lipid carriers offer the next evolution of liposomal encapsulation by adding another layer of hydrogel polymer encasing the bilayered liposome [286]. An added advantage of such carrier technology, which is also referred to as ‘solid lipid nanoparticles’ is reducing the necessity of an organic (oil) phase for sunscreen formulation. Thus, formulations may begin resembling hydrogels with the complete absence of greasiness, greatly improving the aesthetic acceptance of sunscreens for the general consumer.

The above methodologies, which have become mainstream in pharmaceutical and biotech-based parenteral therapies, represent realistic advances for sunscreen formulation technology in the near future.

4. Sunscreen Filters

The key ingredient in a sunscreen formulation is the UV filter. UV filters are either organic (carbon-based) or inorganic, where organic UV filters absorb the UV and convert it to heat and inorganic UV filters absorb the UV and reflect and scatter it [287]. To provide protection from the radiation of the relevant UV region they will have to do so from 280–400 nm [288]. Most organic filters provide protection in the UVB or UVA spectrum, while the inorganic filters zinc oxide and titanium dioxide offer broad-spectrum protection. Due to the limited absorption wavelengths of most organic UV filters, multiple UV filters have to be added to a sunscreen formulation to obtain a broad spectrum protection [289].

Titanium dioxide and zinc oxide have been used for 25+ years in micronized forms as sunscreen actives for their physicochemical properties absorbing UVR and visible light [290]. The light scattering and absorption occurs via electron excitation in their semiconductor band structure [291]. The two filters were commonly used together in formulations due to titanium dioxide primarily absorbing in the UVB range and zinc oxide exhibiting more broad-spectrum coverage across UVB and UVA ranges. Their capacity to function effectively as UV absorbers is heavily influenced by crystal phase, particle size, and formulation-specific factors including the surrounding material [291,292]. Historically, success in enhancing the aesthetics of formulations containing inorganic UV filters has been achieved using nanoparticles, specifically by reducing zinc oxide particle size from 200–400 nm to 100 nm [293]. These smaller particles hardly reflect visible light, resulting in formulations that appear smoother and more transparent on the skin while maintaining UV-blocking capabilities. Titanium dioxide particles smaller than 100 nm and zinc oxide particles smaller than 200 nm readily transmit visible light, making them appear transparent [291].

Organic UV filters are aromatic molecules with extended π-conjugation that absorb solar energy mainly through π → π*—and, when lone pairs are present, n → π*—electronic transitions [294,295]. The part of the spectrum they cover is governed by the length of the conjugated pathway, the electron-donating or -withdrawing character of substituents, and the planarity of the chromophore, factors that together set the energy gap between the highest-occupied and lowest-unoccupied molecular orbitals; a smaller gap pushes absorption toward longer wavelengths [294,295]. Octinoxate, an alkyl p-methoxycinnamate, carries a phenyl-propenoate chromophore whose para-methoxy donor and conjugated C=C–C=O chain resonate at roughly 310 nm, making it a UVB-selective absorber [296]. Oxybenzone’s two benzene rings are cross-conjugated through a carbonyl bridge; this split π-system produces bands near 288 nm and 326 nm, extending protection into short-wave UVA [297]. Avobenzone, a dibenzoylmethane derivative, forms a stabilized enol that delocalises across the β-diketone core and shifts absorption deep into the UVA1 window (λ_max ≈ 360 nm); the same keto–enol tautomerism, however, renders it photolabile unless paired with quenchers or stabilising co-filters [298]. Triazine-based filters such as bemotrizinol and phenylene bis-diphenyltriazine deliver UVB-to-UVA1—and, for the latter, even high-energy visible (400–450 nm)—cover age with photostability: their highly conjugated, conformationally locked cores dissipate excitation energy ultrafast, so only trace photodegradation is observed even after intense irradiation [299,300,301,302]. Because unstable filters can lose efficacy and generate reactive photoproducts, modern sunscreens deliberately combine agents whose spectral ranges and stability profiles complement one another [303].

Multiple organic UV filters have been approved globally for use in sunscreens, although the number and specific compounds vary by region. At least 40 organic UV filters have been approved across global regulatory systems [304,305,306,307]. They can broadly be grouped as benzophenones, cinnamates, PABA derivatives, salicylates, and others. Not all of them are photostable which especially in the USA is a bigger issue as there are only 15 approved organic UV filters and the two, avobenzone and menthyl anthranilate (meradimate), that absorb in the UVA range only provide partial UVA1 protection [308,309]. The main challenges with some of the currently available UV filters are narrow absorption wavelength range, poor photostability, and potential toxicity to humans and/or the environment [310].

There has been an increased use and thereby release of UV filters into the environment and over at least the past decade there has been a growing concern about the environmental impacts of UV filters. This has in part caused a shift in the sunscreen industry where the use of some UV filters have been banned in parts of the world [288]. Consumers are demanding options perceived as safe, avoiding organic UV filters such as oxybenzone and octinoxate, which have raised concerns about toxicity (e.g., endocrine disruption) and environmental impact (e.g., coral bleaching) [311,312,313]. Even for the inorganic UV filters concerns have been raised about the use of nanoparticle-sized inorganic filters, as their potential penetration into the skin causing long-term effects remain under investigation [314,315]. We refer to a recent review on the subject that covers the environmental concerns in detail [288].

Sunscreens, especially in the USA where there is a smaller selection of approved UV filters compared to other countries, are needed that offer a holistic protection against the sun while taking into consideration consumer’s demands for safer, eco-friendly, and multifunctional photoprotection solutions. Additionally filters that adequately protect against UVA1 radiation as well as visible light are needed [316].

Ensulizole was the most recent UV filter to be approved in the USA, this was in 1999 [317]. Since then, many advances in development of novel UV filters have been made and introduced into markets outside the USA. The UV filter phenylene bis-diphenyltriazine was recently introduced into the EU market and is a broad spectrum organic UV filter that also absorbs visible light between 400–450 nm and can reflect blue light with peak reflectance around 450 nm [299]. Additionally, its efficacy against blue light-induced DNA damage through inhibition of 8-oxo-7,8-dihydroguanine formation was demonstrated in reconstructed human skin [318]. Methoxypropylamino cyclohexenylidene ethoxyethylcyanoacetate (MCE) with peak absorption at 385 nm, another recently introduced UV filter, was developed to fill the gap organic UV filters leave at 360–400 nm wavelength of the UVA1 region [319,320]. In an 8 week human study, compared to the reference sunscreen product with SPF50, reduced pigmentation and reduced facial skin aging was observed in volunteers using the sunscreen product containing MCE [319].

Solid lipid nanoparticles have been incorporated into sunscreens for several decades as efficient, low-irritation vehicles for delivering active UV filters and other ingredients to the skin. More recently, they have gained recognition for their ability to partially absorb and reflect UV light through their highly crystalline, light scattering structures [321]. Studies have reported optimal SPF enhancement when lipid content exceeds 10% [321] and particle sizes are maintained between 500–1000 nm [322]. Moreover, combining solid lipid nanoparticles with other molecular sunscreens has been shown to improve overall photoprotection [323]. While used in modern sunscreens for their delivery attributes, they are not classified as UV filters.

Another indirect approach to enhancing SPF is the use of SPF boosters. Boosting the UV filter system refers to attaining a better SPF performance with less UV filter, which can lower costs, minimize white cast, and reduce potential irritation [324]. SPF boosters act through various mechanisms, including scattering UV light, stabilizing emulsions, and providing antioxidant benefits [325]. The term encompasses a diverse group of ingredients that either mimic UV-active properties, or enhance the solubility, dispersion, film stability and thereby, efficacy, of UV actives. Recent developments in SPF booster technology have introduced multifunctional materials capable of enhancing sunscreen efficacy while reducing active filter concentrations. Layered double hydroxide (LDH) platelets, such as Mg₂Al-LDH, have demonstrated significant SPF enhancement through UV scattering mechanisms [326]. Natural compounds like Polypodium leucotomos extract have also shown booster effects, improving both SPF and UVA protection factors while providing some skin benefits [327]. Lignosulfonate, a byproduct of wood pulp processing, has been shown to increase SPF from an average of 27.22 to 78.96 when added at 5% to a sunscreen formulation containing bemotrizinol and diethylamino hydroxybenzoyl hexyl benzoate [328], and also improved formulation photostability likely due to its radical scavenging properties. Additionally, Bacillus lysate derived from research aboard the International Space Station was shown to increase SPF by 33% (from an approximate average of SPF 29 to 38) when incorporated at 3.5% into a sunscreen formulation containing avobenzone, octocrylene, homosalate, and ethylhexyl salicylate [329]. These innovations reflect a growing trend toward enhancing sunscreen efficacy through novel and often naturally derived additives.

Nature has developed a range of effective UV filters and a promising family of molecules comprises the mycosporine-like amino acids (MAAs) and the closely related molecule gadusol that have been reviewed extensively [330,331,332]. Originally discovered in marine organisms over 40 years ago, MAAs have evolved as a natural defense mechanism against UVR and oxidative stress [333]. These molecules exhibit unique photophysical properties, including high extinction coefficients which allow them to absorb UV light efficiently across 310–362 nm [334]. This ability arises from their distinct chemical structure: small, water-soluble scaffolds featuring either a cyclohexenone or cyclohexenimine chromophore substituted with amino acids or imino alcohols [332]. Such substitutions fine-tune their absorption maxima and influence their biological activity. The mechanism involves the dissipation of absorbed UV energy as heat, preventing the formation of harmful ROS [335]. Ultrafast internal conversion, driven by the rigidity and electronic symmetry of the chromophore, underpins this rapid energy dissipation and makes MAAs highly photostable even under intense UV exposure [336,337]. Beyond their UV-absorbing capabilities, MAAs possess biological properties. They act as potent antioxidants, scavenging ROS and reducing oxidative stress, and are anti-inflammatory [334,338,339]. Structural diversity among MAAs—such as in porphyra-334, shinorine, or mycosporine-glycine—also underlies differences in these biological effects, positioning them as dual-function ingredients capable of both photoprotection and skin repair [334]. Additionally, MAAs have been shown to promote cell proliferation and enhance the skin’s natural repair processes [330,340], while their ability to neutralize H₂O₂ further underscores their potential as multifunctional ingredients in modern sunscreen formulations [331,332]. These molecules are not yet available on the market in their pure form due the difficulty in chemically synthesizing them and challenges in economical production of the compounds via biotechnological processes, covered later in this review.

Enhancing Photoprotection with Non-Filter Approaches

Standard UV filters and safe sun practices effectively prevent sunburn (erythema), but they don’t provide complete protection against all the sun’s damaging effects, including DNA damage and harm from ROS. Sunscreens, or cosmetic products used in combination with sunscreens, containing additional cosmetic active ingredients may contribute to mitigating these damaging effects. Additionally, consumers are increasingly demanding multifunctional products that not only provide UV protection, but also address skin-aging and provide skin-repairing benefits [341].

Antioxidants can address some of these demands as they are key to reducing oxidative stress, where commonly used antioxidants include vitamin C and vitamin E [342]. There is published research on thousands of ingredients that are able to impact the biological response of the skin to sun exposure [316]. The majority of these compounds do not have sufficient scientific data to support their protective efficacy and for many only very limited research has been conducted, however a recent review assessed the published literature up until the year of 2023 and categorized them [316]. 85% of the ingredients had very weak or weak evidence and only 148 out of 1750 ingredients were supported by a clinical study [316]. The ingredients with the strongest evidence to support their efficacy in their role in mitigating UV-damage are vitamin C—most effective against oxidative stress, the DNA repair enzyme photolyase—prevents apoptosis and reduces DNA damage, vitamin B3—most effective at reducing UV-induced immunosuppression, the polyphenol epigallocatechin—anti-inflammatory, vitamin E—limits erythema, isobutylamido thiazolyl resorcinol—best supported for depigmenting hyperpigmentation, and N-acetyl-L-cysteine—prevents photoaging through ROS scavenging [316]. Research on ingredients that absorb UVR, shield against UV damage, or repair UV-induced harm continues to evolve with new findings published regularly.

As an example α-arbutin (4-hydroxyphenyl-α-glucopyranoside), known primarily for tyrosinase inhibition and skin lightening, has demonstrated some ability to mitigate UVB and UVA damage [343,344,345]. In mice, application of α-arbutin after UVB exposure reduced the expression of inflammation markers (TNF-α, IL-6, IL-1β), increased the expression of COL-1 thereby promoting collagen synthesis and decreased erythema, wrinkles, and epidermal thickness of the skin on the back of mice [343]. It protects against UVA damage by activating the SIRT3/PGC-1α pathway, enhancing mitochondrial function and reducing ROS [344]. In mouse skin fibroblasts, α-arbutin alleviates UVA-induced DNA damage and mitigates apoptosis by reducing ROS production, regulating collagen metabolism through the AKT/GSK3β and TGFβ/SMAD pathways [345]. A challenge for formulation chemists is to ensure the penetration of α-arbutin into the skin for optimal efficacy as it due to its hydrophilic properties penetrates poorly [346]. Another compound, the antioxidant p-coumaric acid was recently shown to prevent inflammaging and senescence caused by oxidative stress [347]. A human study demonstrated that pretreatment with p-coumaric acid, alone or combined with niacinamide, significantly mitigated UV-induced erythema, barrier disruption, and inflammation (reduced IL-1RA/IL-1α levels) in skin [348].

The use of topical probiotics and prebiotics to enhance the skin’s natural defenses against UVR have also been explored [349,350,351]. Zhang et al. reported that probiotics from high-altitude Tibetans, constantly exposed to high doses of UVR, showed promising results repairing UV damage via the metabolic pathway of carotenoid biosynthesis [352]. Their results provide a new potential skin probiotic for UV-derived disease prevention. Moreover, formulations containing Lactobacillus strains have been shown to reduce UV-induced inflammation and oxidative stress [353]. Ho et al. demonstrated that the treatment with Lactobacillus rhamnosus fermented jasmine extract can slow down collagen breakdown, premature aging, and skin cell aging by effectively ameliorating UVB/H₂O₂-induced dermal cell aging [354]. Lactobacillus iners KOLBM20, isolated from human skin, exhibits anti-photoaging benefits by inhibiting MMP-1 expression and reducing pro-inflammatory factors (TNF-α, IL-1β, IL-6, PGE2) induced by UVB irradiation. This was validated in human skin fibroblasts by demonstrating that KOLBM20 lysate suppresses the ERK, JNK, and p38 signaling pathways [355].

Cosmetic actives demonstrate potential for augmenting the skin’s natural defenses against solar radiation. However, scientific validation is crucial, as many of these compounds lack sufficient evidence supporting their efficacy in this context. Furthermore, optimization of formulations to ensure effective cutaneous delivery is paramount to realizing their potential for meaningful photoprotection.

5. Assessing Sunscreen Efficacy

The measurement of SPF has evolved significantly over the years, transitioning from primarily in vivo methods relying on human volunteers and determination of the MED of UVR, to increasingly sophisticated in vitro techniques [7]. While the in vivo method was the gold standard for many years, it is time-consuming, expensive, and raises ethical concerns due to intentional UVR exposure of volunteers and its adverse effects [356]. In response, researchers developed in vitro methods to simulate SPF measurements using artificial substrates and spectrophotometry. Early methods included a measured accumulation of UV dosage up to one MED being transmitted through a sunscreen film applied to a substrate of ex vivo skin [357]. Current methods include the use of other substrates, such as sandblasted and molded polymethylmethacrylate (PMMA) plates to mimic the texture of skin [358]. Both the International Organization for Standardization (ISO) and the European Cosmetic, Toiletry and Perfumery Association (COLIPA) have widely used guidance on in vitro UV filtration testing that has been validated across numerous testing institutions. In vitro methods are widely used to predict the UV filtration component of SPF prior to in vivo clinical trials. However, it should be noted that non-permeable substrates such as PMMA cannot predict the impact of a specific sunscreen product formulation upon UV filter absorption into the skin and the resulting effect upon UV filtration efficiency and predict any impact of the product formulation upon the biological erythema response. Moreover, some of the in vitro methods struggled to correlate well with in vivo results due to differences in application thickness, substrate texture, and UV scattering. Advances in optical instrumentation and substrate design have improved the accuracy of in vitro SPF testing. The introduction of standardized protocols, such as the ISO 23698 [359] for in vitro SPF testing and ISO 24443 for in vitro UVA protection [360] provided a framework for harmonizing methods globally.

The latest milestone is the ISO 23698 standard, implemented in December 2024, which specifically addresses in vitro SPF measurement [359]. This standard builds on decades of scientific progress, beginning with the pioneering work of Groves [361], Cumpelik who introduced the first spectroscopic SPF measurement [362], and Petro [363]. This work laid the foundation for non-invasive SPF assessment, shifting the focus toward instrumental methods. The contributions of Pissavini et al. in 2018 marked a significant leap forward by refining in vitro techniques to achieve high correlation with in vivo results [364]. The ISO 23698 standard incorporates novel techniques, such as robotic sunscreen application to ensure consistent thickness and high-resolution spectrophotometry to account for UV scattering, absorption, and photodegradation of sunscreens under UV exposure. By introducing complex correlation factors and validation criteria, this method has demonstrated a strong alignment with in vivo SPF measurements, reducing the reliance on human subjects [359]. The evolution of SPF measurement reflects a broader trend toward more ethical, reproducible, and precise testing methods. This progress underscores the importance of interdisciplinary collaboration in advancing photoprotection science, ensuring that sunscreen formulations are both effective and safe for consumers.

In the US, in vivo SPF testing follows guidance from the Food & Drug Administration (FDA) as well as international methodologies. In the M020 OTC Monograph for substantiating SPF claims, specifications are outlined for the requisite UV source, solar simulator, application method on human subjects, UV exposure, and the calculation for obtaining an SPF value. Internationally, COLIPA published a joint international SPF methodology with the Japan Cosmetic Industry Association (JCIA), the Cosmetic, Toiletry, and Fragrance Association (CTFA) (now the Personal Care Products Council, PCPC) and CTFA South Africa [365]. The ISO offers their method, 24444:2019 [366], which is known as the gold standard for in vivo SPF determination, using standardized solar-simulated light sources, that is very similar to the FDA OTC Monograph [358]. With sunscreen product testing comes an inherent variability of SPF results between test subjects and laboratories [358], which has led to a need for increased testing. Studies have shown that SPF claims should be based on data from three or four different institutions for the best accuracy [367] and not from a single laboratory [368].

UVA protection in sunscreens is evaluated through the UVA Protection Factor (UVA-PF), determined by in vivo and in vitro methodologies. In vivo measurements rely on observing the tanning response of the skin, using Immediate Pigment Darkening (IPD) and Persistent Pigment Darkening (PPD) as endpoints [369]. PPD, which assesses skin tanning hours after UVA exposure, is the basis for the Protection Grade of UVA (PA) rating system in Asian countries and has been incorporated into international standards, including ISO 24442 [370] for measuring UVA-PF in vivo [371]. In vivo methods involve exposing human subjects (Fitzpatrick skin types II-IV) to UVA radiation and are the basis of testing standards in many different countries [370,372,373].

Recognizing limitations of in vivo testing, regulatory bodies are increasingly acknowledging in vitro UVA testing methods, which use artificial substrates, a sunscreen film, and a spectrophotometer [374,375,376]. The COLIPA in vitro UVA method utilizes PMMA plates and measures UVA-PF and critical wavelength (CW), requiring products to meet both UVA-PF/SPF in vivo ratio ≥ 1/3 and CW ≥ 370 nm [374,377]. ISO 24443 for determination of UVA-PF in vitro is the international standard similar to COLIPA and has been adopted by many countries including Australia, South Africa, and countries of the EU for their testing [360,378].

The FDA method (FDA 21 CFR 201.327 [379]) also widely adopted, shares similarities with COLIPA and ISO 24443 but differs in parameters and allows sunscreen products with CW ≥ 370 nm to be labeled as broad spectrum, irrespective of the UVA-PF [360,380]. A 2017 study showed that sunscreens meeting the FDA requirement may still fail the ISO requirement for UVA-PF demonstrating a key difference in broad spectrum accreditation [380]. Overall, the selection of a specific method and its associated criteria can significantly impact the classification and labeling of sunscreen products.

6. Regulatory Landscape and UV Filter Considerations

Globally, sunscreen products are not regulated in the same manner, with varying classifications, ingredient approvals, and testing requirements. In the EU, sunscreens are classified as cosmetics, with a broader range of approved ingredients. Products must meet strict safety assessments, and labeling must include SPF and UVA protection claims, as stipulated by Regulation (EC) No. 1223/2009 of the European Commission [381]. Japan treats sunscreens as quasi-drugs, requiring rigorous testing and approval for certain products, including specific formulations for SPF and UVA protection. In Canada, sunscreens are classified as cosmetics under Health Canada, with a pre-market notification system and regulations on ingredient use. Products must also adhere to specific SPF and broad-spectrum labeling [381].

China requires sunscreens to undergo safety evaluations and approval by the National Medical Products Administration, which began a project back in 2013 to revise and replace the previous Regulations on Hygiene Supervision of Cosmetics (CHSR). The new regulations on the Supervision and Administration of Cosmetics were issued in 2020 by the State Council of China to accommodate the substantial growth experienced by the cosmetics industry since CHSR was published in 1989. Sunscreens remain in the category of special cosmetics under the new regulation, with allowed UV filters listed in the Safety and Technical Standards for Cosmetics [382]. Australia applies a dual regulatory model depending on the intended use of the product. Primary sunscreens—those with sun protection as their main function and SPF above 4—are considered therapeutic goods and must be listed in the Australian Register of Therapeutic Goods (ARTG), meeting rigorous testing requirements outlined in AS/NZS 2604:2021. Secondary sunscreens, such as moisturizers with SPF up to 15, are regulated as cosmetics under the Australian Industrial Chemicals Introduction Scheme (AICIS) and must comply with specific labeling, formulation, and packaging standards [383].

The Association of Southeast Asian Nations (ASEAN) includes the countries Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Vietnam. In the ASEAN regions sunscreens are regulated as cosmetics under the ASEAN Cosmetic Directive, which closely mirrors EU legislation. Products must meet GMP standards, adhere to labeling rules, and include only UV filters approved in the directive’s annexes [384].

In the Southern Common Market (MERCOSUR) countries—Argentina, Brazil, Paraguay, and Uruguay—sunscreens are classified as cosmetic products and regulated under harmonized rules influenced by the EU model [385]. MERCOSUR/GMC/RES. No. 44/2015, amended by Resolution No. 14/2021, outlines permitted UV filters, concentration limits, and labeling requirements. In Brazil, its national health authority, ANVISA, enforces these regulations, requiring safety and efficacy assessments for all sunscreen products [385].

In India, sunscreens are classified as cosmetic products under the Drugs and Cosmetics Act, 1940, and are regulated by the Cosmetics Rules, 2020 [386,387]. All imported or domestically manufactured sunscreens must be registered with the Central Drugs Standard Control Organization prior to market entry. The registration process involves submitting product safety data, labeling information, and ensuring compliance with relevant standards [387]. Specifically, sunscreens must adhere to the Bureau of Indian Standards guidelines for SPF and UVA protection testing, which incorporate international standards such as ISO 24444 and ISO 24442 [388].

Gulf Cooperation Council (GCC) countries, including the United Arab Emirates (UAE), follow a unified regulatory framework for cosmetics, for cosmetics under the GCC Standardization Organization (GSO) [389,390]. In the UAE, regulation is overseen by the Ministry of Industry and Advanced Technology (MoIAT, formerly ESMA) and local authorities like Dubai Municipality [391,392]. Sunscreens are classified as cosmetics and must comply with GSO 2237:2012 [393]. Products must be registered, undergo safety testing, and include bilingual (Arabic and English) labeling. Labels must list ingredients, usage instructions, country of origin, and avoid medical claims [392]. Before market entry, products require ECAS certification from MoIAT, and those sold in Dubai must also be registered via the Montaji system [391,392]. Global regulatory processes continue to evolve, with increasing emphasis on ingredient safety and product efficacy, though they vary in the specific designations and testing required for approval [381].

In the USA, the FDA regulates sunscreens (those making claims to protect the skin against UVR) as over-the-counter drugs, requiring safety and efficacy testing for approval and limiting the number of approved active ingredients. According to US law, drug products are “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals” [394]. New drug ingredients therefore undergo extensive reviews before being approved [395]. The 2020 Coronavirus Aid, Relief, and Economic Security Act (CARES Act) enacted in March 2020 in response to the COVID-19 pandemic reformed FDA’s regulatory process for OTC monographs. The CARES Act established deemed final orders which included “generally recognized as safe and effective” (GRASE) conditions [396]. Specific to OTC sunscreen drug products, the deemed final order was to consist of the provisions of the stayed Tentative Final Monograph of 1999 as amended by the Proposed Rule published in 2011 [397]. OTC Monograph M020: Sunscreen Drug Products for OTC Human Use was published in September 2021 in adherence to this requirement. M020 is the current regulatory document governing OTC sunscreen drug products in the US. An important component of M020 is the definition of the “Sun Protection Factor” (SPF) which is defined as a “a measure of how much solar energy (UVB) is required to produce a sunburn on protected skin relative to the amount of solar energy required to produce sunburn on unprotected skin” [13]. SPF as defined in the US is determined clinically using human subjects employing a specific protocol detailed in M020.

Zinc oxide and titanium dioxide are the only two drug actives listed as GRASE Category I. Two of the organic drug actives, para-aminobenzoic acid (PABA) and trolamine salicylate, are proposed as non-GRASE (Category II), and the 12 remaining organic sunscreen drug actives in M020 are proposed Category III because there according to the FDA is insufficient systemic toxicology data to indicate that potential transdermal systemic absorption of these compounds does not present a human health risk [395]. The sunscreen industry in the USA has begun to lean towards the use of primarily inorganic APIs due to the GRASE Category I status [398].

Regarding required SPF testing, there is growing controversy and consumer skepticism surrounding the testing and determination of SPF values on sunscreen drug products, especially whether the standard application amount in vitro and in vivo testing (2 mg/cm²) represents accurate consumer usage. Some studies have suggested consumers only achieve 50% of the labeled SPF in a normal use case [399]. The SPF performance of a sunscreen drug product can be improved by increasing the overall filtration of UVR, or by mitigating the biological response to UV damage, thus reducing erythema in vivo. Improving upon existing formulations for a new product approval can be done by registering a new sunscreen drug active via New Drug Application (NDA), enhancement of UV filtration provided by concentrations of drug actives and combinations thereof approved in the current OTC Monograph through optimization of product formulation (M020 at time of this writing), or by incorporation of cosmetic inactive ingredients that boost SPF efficacy through mitigation of the erythemic biological response to UVR in combination with an approved sunscreen active ingredient in the current OTC Monograph or included in a sunscreen drug product that is the subject of an NDA [396]. Within the rigid regulatory framework and facing consumer needs, formulators and product developers require more sophisticated tools to innovate around the limited active ingredients available and costly (and often variable) testing needed to validate SPF claims for sunscreen products.

7. Next Frontiers in Sun Protection

Recent advances in computational power and interdisciplinary research have opened exciting new avenues for the development of innovative and sustainable sun protection strategies. The convergence of fields like artificial intelligence, computational modeling, and biotechnology can accelerate the discovery and optimization of both novel UV filters and enhanced delivery systems. These approaches promise not only to improve the efficacy and personalization of photoprotection but also to address pressing environmental concerns associated with traditional sunscreen ingredients and manufacturing processes. The following sections explore these two transformative areas, highlighting the potential of artificial intelligence (AI) to revolutionize sunscreen formulation and the power of biotechnology to unlock sustainable sources of next-generation photoprotective compounds.

7.1. AI Applications in Sunscreen Development

Emerging technologies are revolutionizing sunscreen formulations, enhancing their efficacy, safety, and user experience [400]. AI is revolutionizing the development of new molecules and personal care products, and sunscreens are not an exception. AI enables more precise and cost-effective research at an unprecedented speed. AI algorithms analyze large datasets to identify or design novel UV-absorbing compounds and predict their UV absorption spectra, efficacy and safety. For example, machine learning models can screen chemical libraries to discover molecules with optimal photoprotective properties, such as high extinction coefficients and stability under UV exposure [401,402]. Recent advances in computer-aided drug design have demonstrated the potential of AI in designing hybrid compounds, such as resveratrol-avobenzone hybrids, which exhibit broad-spectrum UV absorption and antioxidant activity, making them promising candidates for next-generation sunscreens [403].

AI is also being used to optimize sunscreen formulations by predicting how different ingredients interact and affect product performance, such as SPF value, water resistance, and sensory attributes [404,405]. Simulations of in vitro and in vivo methods to predict SPF in silico are used to supplement the design of sunscreen formulations and predict the SPF value of UV filter combinations. The SPF calculation used is the same as in vitro methods and replaces the measured transmittance value with a calculated transmittance, considering the overall absorbance of the desired UV filters modified to reflect the calibration obtained in vivo [358]. This method is limited by assumptions that must be made regarding film thickness distribution of the sunscreen product, formulation vehicle, application amount and process, and substrate roughness [276]. In silico calculations can, however, be useful in understanding how the previously mentioned aspects will impact an SPF value, as well as indicate where UVB-biased sunscreen products affect the protection profile [357]. A popularly used tool for sunscreen product formulators is the BASF Sunscreen Simulator, used to estimate SPF values using known parameters including UVA protection, photostability, and even emollient interactions with filters. However, when developing novel UV filters, in silico models may require substantial work on the back end to supplement unknown material characteristics that do not yet exist in a database or published literature, especially regarding the prediction of dermal sunscreen active absorption and the pharmacodynamics of the biological response (and potential mitigation) to UV exposure. In summary tools like the BASF Sunscreen Simulator and a similar tool developed by DSM, the DSM Sunscreen Optimizer, leverage AI to model sunscreen film behavior on the skin, enabling formulators to achieve optimal UV protection profiles reducing rounds of trial and error [406].

AI-powered tools are additionally enhancing personalized sun protection by analyzing individual skin types, UV exposure patterns, and genetic risk factors to recommend user specific tailored products [407,408,409,410,411]. The literature regarding AI, machine learning and neural networks used to diagnose skin diseases such as melanoma [412], hyperpigmentation [413], hydration [414], skin barrier function [415], toxicity [416] or other skin conditions [417] is rapidly expanding. These new technologies are no longer of benefit only to companies as they are also being developed for use by the final user. For instance, smartphone apps equipped with AI can assess skin damage through image analysis and provide real-time advice on sunscreen application [418,419,420]. These innovations align with the growing demand for personalized skincare solutions, as highlighted by recent studies on the integration of AI in dermatology and cosmetology [421].

By streamlining the R&D process and enabling personalized solutions, AI is positioned to drive innovation in the sunscreen industry, making photoprotection more effective, accessible, and consumer-centric. The integration of AI into sunscreen development not only accelerates the discovery of new ingredients but also ensures that products meet evolving regulatory standards and consumer expectations for safety, efficacy, biodegradability, and sustainability. As AI continues to evolve, its role in advancing sunscreen technology will likely expand, leading the way for smarter, more adaptive photoprotection strategies in the future [422].

7.2. Biotechnological Production of Sunscreen Ingredients

Biotechnological manufacturing, using wild-type or genetically engineered microorganisms or other cell types to sustainably produce natural products and other chemicals has grown over the past decades and will continue to expand [423]. The advances are fueled by consumer demand for sustainable, safe, and effective ingredients as well as advances in our knowledge of cell biology along with tools allowing for this research, such as faster and more efficient genetic engineering tools, automation, DNA sequencing and synthesis, protein engineering, and AI [423,424].

Biotechnology will also contribute to advances in the suncare industry by enabling both development of (novel) protective molecules and their manufacturing. The use of biotechnology for manufacturing expands production possibilities beyond traditional plant extraction methods and enables manufacturing of highly pure compounds with a consistent product quality. This approach is particularly valuable for compounds that are difficult to synthesize chemically or extract efficiently from natural sources. MAAs exemplify this challenge due to their complex structures, which makes chemical synthesis difficult [425]. Additionally, extracting specific MAAs from natural sources can be problematic due to their typically low concentrations and can make it a challenge to obtain a pure product, which often challenges the commercial feasibility of the product [425].

At least 78 MAAs have thus far been discovered and are characterized by their chemical structure containing either a single-substituted cyclohexanone or a double-substituted cyclohexenimine, however the biosynthetic pathways have not yet been elucidated for many of them [330,426,427]. It has been proposed that MAAs can be synthesized through two distinct biosynthetic pathways. The first pathway proceeds through 3-dehydroquinate (DHQ), a shikimate pathway intermediate, while the second utilizes sedoheptulose 7-phosphate (S7P) from the pentose phosphate pathway (PPP) [330,427]. Both pathways depend on intermediates from glycolysis and the PPP. In the first route, 3-deoxy-D-arabinoheptulosonate 7-phosphate (DAHP) synthase catalyzes the conversion of phosphoenolpyruvate and erythrose 4-phosphate to form DAHP, which DHQ synthase then converts to DHQ. DHQ is further converted through the shikimate pathway to form aromatic amino acids. In the second route, transketolase generates S7P from ribose 5-phosphate and xylulose 5-phosphate in the nonoxidative PPP branch. The S7P is then recycled back to glycolytic intermediates through the combined actions of transaldolase and transketolase, producing fructose 6-phosphate and glyceraldehyde 3-phosphate [330,427].

Microbial heterologous production of MAAs has already been heavily explored. Production of 4-deoxygadusol [428], shinorine [428,429,430,431,432,433], porphyra-334 [428,432], palythine-threonine [428,434], palythine-serine [428], mycosporine-ornithine [435], mycosporine-lysine [435], mycosporine-glycine (MG) [428,432], mycosporine-2-glycine [428,432], and mycosporine-glycine-alanine [428] have been demonstrated.

Some cyanobacteria naturally produce MAAs. The species Synechocystis sp. PCC6803 was engineered to heterologously produce shinorine by introducing the shinorine gene cluster from the cyanobacterium Fischerella sp. PCC9339 along with promoter optimization which resulted in a yield of 2.37 ± 0.21 mg/g shinorine [430].

One study found that by integrating multiple copies of MG biosynthetic genes in Saccharomyces cerevisiae from cyanobacteria, MG could be produced [432]. From MG, shinorine, porphyrra-334, or M2G can be produced by introducing the mysD gene encoding a D-alanine-D-alanine ligase [432]. Homologues of the enzyme MysD from different cyanobacteria demonstrated different substrate preference, specifically towards serine, threonine, and glycine resulting in production of 1.53 g/L shinorine, 1.21 g/L porphyra-334, and M2G [432]. A prediction based on structural homology indicated the substrate specificity of MysD is determined by the omega loop region of 43–45 amino acids from Thermus thermophilus involved in peptidoglycan biosynthesis. The substrate specificities of two MysD enzymes were interchangeable by swapping the omega loop region [432]. Understanding the characteristics of these terminal enzymes is crucial not only for potentially improving production yields, but also for developing a platform strain where new MAAs can be produced by simply swapping the terminal enzymes.

Strain engineering to further increase titers of shinorine has also been described. In S. cerevisiae it was demonstrated that MAAs are primarily produced from S7P in the PPP, rather than from the shikimate pathway [436]. Significant improvements in shinorine production through two key genetic modifications: removing the transaldolase gene (TAL1) and deleting the phosphofructokinase gene (PFK2), each resulting in a 9-fold increase in production. These modifications work through different mechanisms and show additive effects when combined. A particularly significant finding was the discovery of a reversed non-oxidative PPP mechanism. When PFK2 is deleted, accumulated fructose 6-phosphate (F6P) is redirected through this reversed pathway to produce S7P, ultimately boosting MAA production [436]. This finding builds upon and provides experimental evidence for previously theorized but unproven metabolic models. The research also has broader implications for metabolic engineering and commercial applications. The demonstrated ability to redirect metabolic flux through pathway engineering suggests potential applications for producing other S7P-derived metabolites.

Besides biosynthesis of MAAs there are multiple other compounds relevant for sunscreen products that have been produced with microorganisms. This includes production of the molecule gadusol from S7P, which was first demonstrated in S. cerevisiae, by introducing only two heterologous genes encoding the enzymes 2-epi-5-epi-valiolone and O-methyltransferase oxidoreductase from zebrafish [437]. The titer of 20 mg/L is rather low but the startup Arcaea has since been working on further improving the titers to commercialize gadusol [438]. Production of melanin, the “natural sunscreen” of the human skin, using fungal strains without any strain engineering has been demonstrated, where the fungus Amorphotheca resinae was shown to produce up to 4.5 g/L melanin [439,440]. The indole-alkaloid scytonemin is an antioxidant and UV absorber that cyanobacteria produce to protect them from UVR [441]. Its biosynthesis has thus far only been described in cyanobacteria such as Nostoc flagelliforme and Nostoc punctiforme, however an attempt at heterologous production using Escherichia coli was made which only resulted in the scytonemin monomer perhaps due to the lack of the EboABCEF complex [442,443].

Challenges remain in commercializing these biosynthesized compounds. Current MAA titers reported in the literature are too low for commercial viability and would likely require at least a 10-fold or higher increase, with manufacturing volumes in the hundreds to thousands of kilograms to achieve a competitive cost compared to existing UV filters, UV boosters, and cosmetic actives.

Investment in strain engineering is essential, where factors such as host selection potentially determine success or failure. Additionally, the high costs of strain development and scale-up of production present a major hurdle for many companies. Lastly, for some of the novel (natural) products described such as the MAAs, ensuring the stability in cosmetic formulations and meeting stringent regulatory requirements for novel ingredients demands substantial development work and is critical for successful integration into sunscreen products.

Despite these challenges, biotechnology continues to open new possibilities in UV protection, suggesting a future where more effective, sustainable, and biodegradable photoprotective compounds become available. The integration of multiple approaches—from synthetic biology to protein engineering and AI—promises to revolutionize how we protect skin from solar radiation.

8. Closing Remarks

Thanks to advances in our understanding of solar radiation and skin biology, we now have the capability to formulate more effective sunscreens than ever before. However, significant challenges remain, including formulating for broad-spectrum protection against UVA1 and visible light, addressing concerns about the environmental impact of UV filters, and optimizing delivery systems to enhance the efficacy of active ingredients. Despite these hurdles, our current knowledge allows us to develop aesthetically pleasing, and sustainable sun protection strategies.