Artocarpin: Multi-Targeted Mechanisms Against UV-Induced Skin Aging and Its Skin Penetration Enhancement Strategies

Abstract

Artocarpin, a prenylated flavonoid isolated from Artocarpus altilis heartwood, has emerged as a promising multi-targeted bioactive compound for combating UV-induced skin aging. This review provides a comprehensive overview of the molecular mechanisms and photoprotective efficacy of artocarpin across in vitro, in vivo and clinical study, based on the peer-reviewed literature published between 2012 and 2025, retrieved from PubMed, Scopus, and Web of Science. Delivery strategies designed to overcome the inherent physicochemical limitations of artocarpin on skin penetration are also discussed. Artocarpin demonstrates antioxidant effects through both direct free radical scavenging and activation of the Nrf2-ARE pathway, providing sustained cellular defense. Its anti-inflammatory properties target multiple signaling cascades, including the NF-κB and MAPK pathways, effectively mitigating UV-induced inflammatory response. The compound maintains dermal matrix homeostasis by inhibiting matrix metalloproteinase-1 (MMP-1) expression while preserving collagen synthesis and fibroblast mechanical function. Additionally, artocarpin exhibits selective apoptosis modulation, being cytoprotective in normal keratinocytes while acting as pro-apoptotic in damaged or abnormal cells, thereby supporting tissue homeostasis. It also inhibits melanogenesis through anti-inflammatory mechanisms rather than direct tyrosinase inhibition. Furthermore, artocarpin has been shown to induce autophagic cell death in certain cell lines; however, its role in UV-induced skin damages remains to be clarified. Despite these promising biological activities, the poor water solubility (<0.1 mg/mL) and high lipophilicity (log P ≈ 5) of artocarpin significantly limit its skin penetration. Lipid-based delivery systems, including liposomes, transfersomes, ethosomes, and nanostructured lipid carriers (NLCs), are presented as effective strategies to enhance transepidermal delivery, with each system offering distinct mechanistic advantages. Further investigations should prioritize the safety of artocarpin within each delivery system, as well as the synergistic co-encapsulation with complementary natural antioxidants to simultaneously target multiple mechanisms involved in UV-induced skin damage, thereby broadening its application in the cosmeceutical industry.

1. Introduction

As we know, chronological or intrinsic aging generally results from accumulated molecular damage in the body. However, environmental factors can trigger the advanced accumulation of damaged molecules, which we call premature, accelerated or extrinsic aging. Among external or environmental factors, such as ultraviolet (UV) radiation, smoking, harmful microorganisms, and pollution, UV radiation from sunlight (UVA (320–400 nm) and UVB (280–320 nm)) is recognized as the predominant cause of premature skin aging, termed photoaging, which manifests as coarse wrinkles, loss of skin elasticity, leather-like texture, and irregular hyperpigmentation [1,2].

Research shows that intrinsic aging and photoaging share common molecular pathways, including inflammation [3,4], induced apoptosis [5,6,7], elevated matrix metalloproteinases (MMPs) that degrade connective tissue [5,8,9], reduced procollagen synthesis [10,11], and impaired autophagy [5,12,13], all of which are intensified by UV exposure [14].

Within minutes of UV exposure, endogenous photosensitizers in the skin, such as porphyrins [15], melanin [16], and aromatic amino acids [17,18], absorb UV radiation and become excited [19]. The activated photosensitizers then transfer energy to nearby water molecules and oxygen, leading to the formation of reactive oxygen species (ROS), which include hydroxyl radicals (•OH) from water, and singlet oxygen (¹O₂) and superoxide radicals (O₂•⁻) from oxygen. Additionally, reactive nitrogen species (RNS) such as nitric oxide (•NO) and peroxynitrite (ONOO⁻) are generated through interactions between ROS and cellular nitrogen compounds. Generally, the skin possesses an endogenous antioxidants defense system, including enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), and glutathione S-transferase (GST), along with non-enzymatic antioxidants including glutathione, vitamin E, and vitamin C [20]. However, excessive UV exposure overwhelms this defense system, leading to sustained oxidative stress that triggers a cascade of cellular damage mechanisms.

The oxidative stress-induced cascade initiates inflammation through the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways [5,21,22,23]. These pathways upregulate pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and promote overproduction of matrix metalloproteinases (MMPs) [22,24], which degrade collagen, elastin, and other extracellular matrix (ECM) components [8]. Simultaneously, collagen synthesis is reduced through the downregulation of transforming growth factor-β (TGF-β) and procollagen I expression [11]. UV-induced oxidative stress also alters the Wnt/β-catenin signaling pathway, which is essential for skin homeostasis and repair mechanisms [25]. This disruption impairs keratinocyte proliferation and differentiation, further compromising skin barrier function and regenerative capacity [26]. Moreover, prolonged oxidative stress triggers apoptosis induction in key skin cells through the activation of p53 and caspase pathways [7,27,28], while simultaneously causing autophagy imbalance [12,13,29], leading to an accumulation of damaged organelles and proteins.

Regarding the relationship between UV exposure and melanogenesis, inflammatory cytokines create a complex link between inflammation and pigmentation regulation. UV-induced activation of the NF-κB pathway has been shown to promote melanogenesis [30,31], as evidenced by a study demonstrating that NF-κB activation enhances the expression of tyrosinase and premelanosome protein (PMEL) in melanocytes, particularly when combined with UVB irradiation [30]. While TNF-α has been reported to inhibit tyrosinase activity [32], some inflammatory cytokines, such as IL-6, can either activate or modulate melanin production depending on the signaling pathway or conditions. For example, IL-6 acts as a melanogenesis inhibitor in melanocyte while promoting dendrite elongation and melanosome transfer in age spots [30,31,33,34,35]. Moreover, other paracrine mediators released from UV-damaged keratinocytes, such as α-melanocyte stimulating hormone (α-MSH), endothelin-1, and prostaglandins, further stimulate melanocytes and upregulate melanin production [34,36,37], creating a feedback loop between inflammation and hyperpigmentation.

For this reason, besides applying sunscreen alone, a more comprehensive approach to protect skin from UV-induced aging involves topical application of formulations containing compounds that effectively penetrate the skin and can restore skin damage. Such compounds should exhibit multifunctional anti-aging activities, including neutralizing free radicals, enhancing endogenous antioxidant synthesis, modulating inflammatory and MAPK/NF-κB pathways, balancing collagen production and degradation, regulating apoptosis and autophagy homeostasis, and controlling melanogenesis. Based on this approach, several research efforts have focused on identifying active compounds that can prevent or restore age-related skin damage, with particular emphasis on natural-derived substances.

Our studies have demonstrated that extracts from the Artocarpus genus, particularly Artocarpus altilis, show significant potential as active ingredients for preventing and reversing skin aging. Through comprehensive investigations [38,39,40,41,42], we identified artocarpin, a prenylated polyphenol, as the principal bioactive compound in the diethyl ether extract of A. altilis heartwood, comprising 44–45% (w/w) of the extract. Our findings also revealed that artocarpin exhibits several promising anti-photoaging activities, making it a valuable candidate for cosmetic applications. However, its poor water solubility presents a major limitation, significantly reducing bioavailability and skin penetration. This review therefore focuses on clarifying the mechanisms by which artocarpin isolated from A. altilis heartwood prevents and/or reverses UV-induced skin aging, while also exploring strategies to enhance skin penetration and optimize its efficacy in cosmetic formulations.

2. Source of Artocarpin and Its Physicochemical Properties

Artocarpus altilis (synonym: Artocarpus incisus), commonly known as breadfruit, belongs to the Moraceae family. This species is widely distributed throughout tropical regions, including Thailand, where it is locally known as ‘Sa-Ke’ (Figure 1) and its fruit serves as a traditional food source. The heartwood of A. altilis from Okinawa, Japan has been reported to contain several flavonoids with tyrosinase inhibitory activity, including artocarpin (Figure 2A), artocarbene (Figure 2B), artocarpesin (Figure 2C), norartocarpanone (steppogenin) (Figure 2D), dihydromorin (Figure 2E), and chlorophorin (Figure 2F), suggesting potential as whitening agents in cosmetics [43]. Although tyrosinase inhibitory activity screening indicated that artocarpin is not a potent tyrosinase inhibitor, it demonstrated a notable skin-lightening effect in guinea pigs with UVB-induced hyperpigmentation [44], providing preliminary evidence for its cosmetic application. Beyond crude extracts, purified artocarpin preparations can achieve concentrations of 88–99% (w/w), depending on the purification process [38,39,45]. Artocarpin has also been identified in other Moraceae species, including A. heterophyllus (jackfruit), A. kemando Miq., and A. chempeden.

The physicochemical properties of artocarpin influence its biological activity and cosmeceutical applications. Physically, artocarpin exists as a yellow crystalline solid at room temperature, with a molecular weight of 436.5 g/mol and the molecular formula C₂₆H₂₈O₆ (Figure 2A). Its structure features a flavonoid backbone with two prenyl side chains (3-methyl-1-butenyl and 3-methyl-2-butenyl groups) that contribute to its lipophilic character and unique biological properties. Consequently, artocarpin exhibits poor aqueous solubility (<0.1 mg/mL) but dissolves readily in organic solvents such as ethanol, methanol, dimethyl sulfoxide, chloroform, and ethyl acetate. Its high lipophilicity is reflected in a calculated log p value of approximately 4.99 [46], which limits skin penetration, as compounds with log p values exceeding 3 tend to diffuse poorly through the hydrophilic viable epidermis, ultimately reducing bioavailability [47]. The melting point of artocarpin ranges from 168 to 174 °C [48], indicating relatively high thermal stability. However, when applied to the skin, this high melting point results in reduced molecular mobility and slower dissolution at physiological skin temperature (32 °C) [49], which may further limit its release from topical formulations and subsequent permeation into the skin. Additionally, the phenolic hydroxyl groups in its structure render artocarpin susceptible to oxidation, particularly in alkaline environments. These physicochemical characteristics collectively inform formulation strategies for developing artocarpin as a topical agent for skin protection and anti-aging applications.

3. Multifunctional Activity of Artocarpin Against UV-Induced Skin Aging

3.1. Antioxidant Activity

Artocarpin exhibits moderate antioxidant activity as demonstrated by various in vitro chemical studies. When tested at 95% purity, artocarpin showed IC₅₀ values of approximately 700 μmol/L (305.6 μg/mL) for hydroxyl radical scavenging and 22 μmol/L (9.6 μg/mL) for ABTS radical scavenging, while ascorbic acid (the positive control) demonstrated IC₅₀ values of approximately 295 μmol/L (52 μg/mL) and 19 μmol/L (3.4 μg/mL) in the same assays, respectively [50]. A separate study found that 88% pure artocarpin had an IC₅₀ of approximately 132 μg/mL for DPPH radical scavenging, compared to the IC₅₀ of ascorbic acid at approximately 5 μg/mL [38]. These IC₅₀ values indicate slower reaction kinetics with free radicals of artocarpin. This may be attributed to several factors related to its chemical structure [51]. Although artocarpin possesses hydroxyl groups capable of donating hydrogen atoms to neutralize free radicals, the number and positioning of these groups may not be optimal compared to more potent antioxidants such as ascorbic acid. Additionally, the large molecular structure of artocarpin may restrict its ability to access and interact with free radicals in certain condition.

However, studies using in vitro cell-based assays demonstrated that pretreatment of immortalized human keratinocyte cell line, HaCaT with artocarpin significantly decreased levels of ROS and nitrite (a major metabolite of nitric oxide, NO) in cells exposed to UVB radiation [27]. Additionally, in vivo research on UVB-induced skin damage in mice showed that topical application of 0.05% artocarpin significantly decreased ROS levels and lipid peroxidation compared to control mice receiving UVB irradiation with only vehicle application [52]. These findings demonstrate the photoprotective effects of artocarpin against UVB-induced skin damage mediated by generated ROS and RNS (reactive nitrogen species). In general, under normal physiological conditions, natural metabolic processes generate free radicals that are neutralized by endogenous antioxidant systems. When this equilibrium is disrupted in skin tissue due to external stressors such as UV radiation, excess free radicals accumulate, causing oxidative damage to cells and tissues. Prolonged oxidative stress leads to cellular degeneration and accelerated aging. Therefore, both direct antioxidant activity through free radicals scavenging and the ability to maintain or enhance endogenous antioxidant levels are crucial for mitigating oxidative stress. Although artocarpin exhibits relatively modest direct free radical scavenging activity in chemical assays, a study in paracetamol-induced liver damage in rats suggests that natural extracts containing artocarpin can significantly enhance endogenous antioxidant systems such as superoxide dismutase (SOD) [53]. This enhancement may contribute to the observed reduction in free radicals accumula-tion and their interaction products in skin cells and tissues exposed to UV radiation. The enhancement mechanism possibly operates through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the subsequent upregulation of the antioxidant responsive element (ARE) pathway [54,55]. The indirect antioxidant mechanism may provide more sustained protection against oxidative damage than direct ROS scavenging alone, potentially making artocarpin a valuable compound for skin photoprotection and anti-aging applications.

3.2. Anti-Inflammatory Activity

Our previous study demonstrated that the diethyl ether extract of A. altilis heartwood (50 µg/mL, containing approximately 88% artocarpin) significantly attenuated the UVB-induced production of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in keratinocytes in an in vitro UVB-irradiation model [38]. Upon UVB exposure, keratinocytes, the predominant cell type in the epidermal layer of skin, serve as primary mediators of cutaneous inflammation through the release of these pro-inflammatory cytokines. This inflammatory cascade directly contributes to the characteristic manifestations of chronic UV exposure, including erythema, edema, and epidermal hyperplasia. In another study investigating UVB-induced cutaneous damage in vivo, topical application of 0.05% artocarpin (purity not specified) demonstrated significant protective effects against UVB-induced histopathological alterations in hairless mouse skin. These protective effects included the prevention of desquamation, epidermal hyperplasia, and the formation of sunburn cells [52]. The underlying mechanisms extend beyond the previously described antioxidant properties (reduction in reactive oxygen species and lipid peroxidation) to include significant anti-inflammatory activity via downregulation of TNF-α and IL-1β. This cytokine modulation subsequently leads to a decreased expression of downstream inflammatory mediators, including cytosolic phospholipase A2 and cyclooxygenase-2 (COX-2) [52]. Similar cytoprotective effects have been observed in in vitro pollution-induced damage models using the methanolic extract of A. altilis containing 22.5% (w/w) artocarpin. Pretreatment of HaCaT keratinocytes with this extract at concentrations of 2.5 and 5 µg/mL significantly reduced TNF-α and COX-2 expression [56].

At the molecular level, excessive UVB exposure triggers several signaling responses that cause morphological and biochemical changes in skin cells. Free radicals and NO generated after UV exposure mediate the phosphorylation of protein kinases, MAPKs. These MAPKs control the expression of transcription factors such as nuclear factor-κB (NF-κB), which regulates inflammatory gene expression. The phosphorylation of these protein kinases stimulates NF-κB to promote the production of inflammatory cytokines. Artocarpin exerts its anti-inflammatory effects primarily through the inhibition of the NF-κB signaling pathway by modulating phosphorylation of p38 MAPK, a key upstream regulator of NF-κB, as demonstrated in a study using UVB-irradiated HaCaT cells in vitro [45]. Moreover, another study reveals that artocarpin exhibits potent inhibitory activity on NO production in RAW264.7 lipopolysaccharide (LPS)-activated mouse macrophage cells [57]. When macrophages are exposed to LPS, a component of gram-negative bacterial cell walls, they recognize this pathogen-associated molecular pattern via Toll-like receptor 4 (TLR4). This recognition initiates a complex signaling cascade that ultimately leads to the activation of NF-κB. Artocarpin may interfere with this pathway by preventing the phosphorylation and degradation of inhibitory κB (IκB), thereby blocking NF-κB translocation to the nucleus. Consequently, this would suppress the transcriptional activation of the inducible nitric oxide synthase (iNOS) gene, which encodes the enzyme responsible for NO production during inflammatory responses.

Further evidence of the anti-inflammatory activity of artocarpin comes from a study in immune phagocytes isolated from the blood of healthy volunteers, in which artocarpin isolated from A. heterophyllus heartwood suppressed inflammatory processes comparable to reference pharmaceutical agents [58]. These processes include chemotaxis, phagocytosis, ROS production, and myeloperoxidase activity. Recent molecular mechanistic studies in cancer stem cells derived from a lung adenocarcinoma cell line (H460) have demonstrated that artocarpin inhibits the Wnt/β-catenin signaling pathway through direct binding interactions with Wnt and β-catenin proteins, thereby preventing TCF-4/β-catenin complex formation [59]. The Wnt/β-catenin pathway regulates numerous gene transcription events, including those governing pro-inflammatory mediator expression [26,60].

The multi-targeted anti-inflammatory profile of artocarpin enhances its therapeutic potential by addressing inflammatory processes at multiple molecular and cellular levels. This comprehensive approach may yield more effective outcomes in complex conditions such as UV-induced skin damage, where multiple inflammatory pathways are simultaneously activated.

3.3. Collagen Production and Degradation Inhibition

UV radiation activates multiple signaling cascades after skin exposure, predominantly through the extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK pathways [23,45,61]. This activation upregulates critical transcription factors AP-1 and NF-κB, which function as master regulators of the photoaging process. Upon activation, these transcription factors trigger a wide range of cellular responses that collectively contribute to cutaneous photodamage. A primary consequence of this signaling cascade is the enhanced expression of matrix metalloproteinases (MMPs), proteolytic enzymes that degrade the structural proteins such as dermal collagen and elastin, which are essential for maintaining skin firmness and elasticity. Concurrently, UV exposure reduces new collagen synthesis and promotes the accumulation of abnormal elastin material, resulting in solar elastosis [11,39,62]. This imbalance between ECM degradation and synthesis leads to the characteristics of wrinkles, laxity, and textural changes observed in photoaged skin.

Our in vitro study on normal skin fibroblasts demonstrated that MMP-1 overexpression was induced by UVA or UVB irradiation and significantly reduced in cells pretreated with 50 µg/mL artocarpin (87–90% purity) [38,39]. However, the extract did not markedly alter procollagen levels in normal fibroblasts. Since wrinkles are a hallmark of skin aging, characterized by diminished elasticity and dermal laxity due to both reduced collagen synthesis and accelerated degradation of the existing collagen network, further investigation was conducted using facial skin fibroblasts isolated from both wrinkled and non-wrinkled regions. Treatment with 50 µg/mL of A. altilis crude extract (containing approximately 45% (w/w) artocarpin) significantly reduced MMP-1 expression while enhancing type I collagen production, particularly in fibroblasts from wrinkled areas [41].

Further evidence of artocarpin on protective effects against UVB-induced mechanical damage was observed in an in vitro UVB-irradiated fibroblasts model. The irradiated fibroblasts exhibited reduced expression of α-smooth muscle actin (α-SMA), leading to impaired migration and decreased contractile ability. These effects were significantly minimized by pretreatment with 50 µg/mL of artocarpin (87% purity) [63]. α-SMA, a key cytoskeletal component, plays a critical role in regulating fibroblast contractility and maintaining the biomechanical properties of the skin [64,65]. These findings collectively demonstrate that artocarpin exerts multifaceted protective effects by (1) preventing UV-induced oxidative stress that triggers collagen degradation through MMP-1 upregulation, (2) restoring the functional capacity of senescent fibroblasts in aged skin regions, and (3) preserving mechanical integrity by preventing UVB-induced α-SMA suppression.

Overexpression of MMP-1 by skin fibroblasts occurs through, at least partially, two primary mechanisms: (1) induction of autocrine IL-6 signaling [66] and (2) stimulation by paracrine pro-inflammatory cytokines, specifically IL-1β, IL-6, and TNF-α, released from keratinocytes [9,22,67]. The observed reduction in pro-inflammatory cytokine secretion, particularly TNF-α and IL-6, in UV-irradiated keratinocytes pretreated with artocarpin suggests that this compound may suppress MMP-1 expression through downstream modulation of the free radical/TNF-α, IL-6/MAPK signaling cascade. A recent investigation using a particulate matter-induced HaCaT cell model demonstrated that pretreatment with methanolic extract of A. altilis containing 22.5% (w/w) artocarpin significantly decreased the expression of key inflammatory proteins, including TNF-α, TNF receptor, and COX-2, while simultaneously reducing MMP-1 expression and enhancing tissue inhibitors of metalloproteinases (TIMPs), particularly TIMP-1 level [56]. TIMPs are endogenous proteins that regulate MMP activity by inhibiting activated MMPs, thereby maintaining the balance between ECM degradation and deposition. This study also revealed that the protective effects against pollution-induced damage were mediated through inhibition of phosphorylation across multiple MAPK family members, specifically ERK, JNK, and p38 pathways. Since particulate matter pollutants induce cellular damage through oxidative stress mechanisms similar to those caused by UV exposure, the protective effects of artocarpin are likely also mediated through the downregulation of the MAPK signaling cascade. This mechanistic similarity between pollution and UV-induced damage suggests that artocarpin may offer protection against various environmental skin stressors that act through oxidative damage pathways.

3.4. Anti-Apoptosis and Apoptosis Induction

Maintaining cutaneous homeostasis requires balanced regulation of proliferation, differentiation, and programmed cell death within epidermal cells. The controlled elimination of damaged cells through apoptosis serves two critical functions: preserving tissue homeostasis and prevention of tumor formation by removing cells with severe genomic damage [68,69]. Excessive generation of ROS and RNS in the skin after repeated or chronic exposure disrupts skin homeostasis through two main mechanisms: direct DNA damage and activation of death receptor-mediated apoptotic pathways. This UV-induced apoptotic response is an evolutionarily conserved protective mechanism that selectively eliminates keratinocytes harboring potentially oncogenic mutations, thereby reducing the risk of malignant transformation [7]. However, excessive keratinocyte death impairs epidermal barrier integrity and function. Furthermore, widespread keratinocyte apoptosis triggers the release of damage-associated molecular patterns [3,68] and pro-inflammatory and inflammatory mediators, including IL-1α/β, IL-6, and TNF-α [28,70,71]. This inflammatory cascade can establish a chronic state of cutaneous inflammation, exacerbating tissue damage and potentially accelerating photoaging. These findings highlight the importance of photoprotective agents that can maintain a balanced apoptotic response, sufficient to eliminate severely damaged cells while preserving overall epidermal integrity and function.

Our previous in vitro study demonstrated that 3.1 μg/mL of artocarpin (approximately 99% purity) exhibits significant cytoprotective activity against UVB-induced apoptosis in HaCaT keratinocytes [45]. Mechanistically, artocarpin attenuated the activation of key pro-apoptotic signaling molecules, including caspase-3, phosphorylated p53, phosphorylated p38 MAPK, and NF-κB p65 subunit [27,45]. Morphologically, artocarpin treatment preserved cellular integrity by preventing characteristic apoptotic features including nuclear condensation and fragmentation, apoptotic body formation, and F-actin cytoskeletal disruption. Within the extrinsic apoptotic pathway, artocarpin modulated death receptor signaling through the downregulation of Fas (CD95) expression, thereby reducing cellular sensitivity to extracellular apoptotic stimuli. Additionally, artocarpin maintained plasma membrane fluidity, preventing the UVB-induced membrane rigidification [45] that typically precedes apoptotic cascade activation. As previously mentioned, artocarpin suppressed TNF receptor surface expression [56], further attenuating extrinsic apoptotic signaling.

The anti-apoptotic activity of artocarpin may be rooted in its antioxidant properties. This antioxidant mechanism extends beyond direct radical neutralization to include the upregulation of endogenous antioxidant defense systems, thereby reinforcing cellular resistance to oxidative insult.

Notably, artocarpin reduced the formation of cyclobutane pyrimidine dimers (CPDs) [27], the predominant UV-induced DNA photoproducts that serve as critical triggers for apoptotic initiation. By preserving genomic integrity, artocarpin prevented the activation of p53-dependent apoptotic signaling pathways that would otherwise eliminate cells with significant DNA damage. This DNA-protective effect represents a crucial upstream mechanism by which artocarpin prevents apoptotic cascade initiation, complementing its direct modulation of apoptotic signaling molecules.

Apart from its anti-apoptotic effects in normal skin cells, artocarpin (e.g., at 10 μM or 4.365 μg/mL, purity > 98%) has demonstrated in vitro pro-apoptotic activity in various cancer cell lines, including non-small cell lung carcinoma (A549) [72], human osteosarcoma (U2OS, MG63, and HOS) [73], glioblastoma (U87 and U118) [74], and human cutaneous squamous cell carcinoma (HSC-1) [75]. The anticancer mechanisms of artocarpin involve the activation of multiple apoptotic pathways. Specifically, artocarpin induces phosphorylation of pro-apoptotic kinases (ERK1/2, p38, Akt) and activates p53-dependent apoptotic signaling. In glioblastoma cells, artocarpin triggers significant mitochondrial dysfunction, characterized by membrane depolarization and increased ROS production. This leads to cytochrome c release and differential regulation of Bcl-2 family proteins, including upregulation of pro-apoptotic Bax and Bad with concurrent downregulation of anti-apoptotic Bcl-2. This selective cytotoxicity represents a key characteristic of promising anticancer compounds, namely the ability to activate death pathways in malignant cells through ROS generation while acting as an antioxidant and enhancing endogenous antioxidant systems in normal cells. This dual nature makes artocarpin particularly interesting as both a potential anticancer agent and a photoprotective compound for skin.

3.5. Autophagy

Autophagy is a fundamental intracellular catabolic process that degrades and recycles dysfunctional cytoplasmic components through the formation and activity of autophagosomes, thereby maintaining cellular homeostasis during stress conditions. This process can promote cellular survival under moderate stress or contribute to cell death when excessively activated [76].

External environmental factors significantly influence autophagy. UV radiation, for instance, induces complex changes in cutaneous autophagy through multiple mechanisms. Initially, acute UV exposure triggers protective autophagic response, which enhances autophagic flux that facilitates the removal of oxidatively damaged proteins and organelles. This mechanism helps maintain cellular integrity by sequestering and degrading oxidized macromolecules and damaged mitochondria that would otherwise activate apoptotic cascade [29,77]. However, chronic or high-intensity UV exposure can compromise autophagic efficiency. Several investigations have demonstrated that chronic UV radiation disrupts both autophagosome biogenesis and lysosomal function in epidermal keratinocytes and dermal fibroblasts, thereby impairing completion of the autophagic cycle [12,13,78]. This dysfunction leads to the progressive accumulation of cellular damage, including oxidized proteins and impaired organelles, which significantly contributes to accelerated photoaging phenotypes in chronically sun-exposed skin.

The antioxidant properties of artocarpin may indirectly influence autophagic processes. By neutralizing ROS, artocarpin potentially modulates redox-sensitive autophagy regulators, including transcription factors such as Nrf2. Activation of Nrf2 enhances the expression of autophagy-related genes and proteins that facilitate autophagosome formation and maturation, creating a mechanistic link between antioxidant activity and autophagy induction [79,80]. Under cellular stress conditions like repeated UV exposure, artocarpin may enhance autophagy through activation of endoplasmic reticulum (ER) stress pathways, as previous research has shown that artocarpin triggers ER stress in osteosarcoma by activating ER stress sensors such as protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) [73]. Artocarpin also influences the calcium signaling pathway in osteosarcoma. Changes in cytosolic calcium concentrations affect calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), which subsequently activates AMPK and induces autophagy [81]. The ability of flavonoids, including artocarpin, to modulate calcium channels suggests that this compound may use calcium-dependent mechanisms to enhance autophagic flux in target cells.

Another study has demonstrated that artocarpin can induce autophagic cell death in human hepatocellular carcinoma cell lines [82]. The anticancer properties of artocarpin possibly mediate through the inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. As a central regulator of cellular metabolism and growth, mTOR typically suppresses autophagy under nutrient-rich conditions. Evidence suggests that artocarpin modulates mTOR activity, potentially by interfering with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway that activates mTOR [75,83]. This inhibition releases the suppression on autophagy initiation complexes, thereby promoting autophagosome formation. Complementary to mTOR inhibition, artocarpin likely activates AMPK, as demonstrated in glioblastoma models [74]. AMPK functions as a cellular energy sensor that regulates autophagy [76,81]. Traditionally, AMPK has been considered a positive regulator of autophagy through direct phosphorylation and activation of Unc-51 like autophagy activating kinase (ULK1), a key component of the autophagy initiation complex [84]. However, recent evidence reveals that AMPK can also inhibit ULK1 activity under certain conditions, particularly during glucose starvation [85,86]. This dual regulatory role suggests that AMPK may function as a modulator that restrains abrupt autophagy induction during energy shortage while preserving essential autophagy components for long-term cell survival. The precise mechanism by which artocarpin influences this AMPK-ULK1 axis in cancer cells needs further investigation.

To our knowledge, there are no published reports on the effects of artocarpin on autophagy in skin cells under both normal and UV-irradiated conditions. It is important to note that the proposed mechanisms of artocarpin-induced autophagy are largely theoretical, extrapolated from studies in cancer cell models. Experiments in normal skin cells are needed and should focus on how artocarpin controls autophagy in the context of skin health and UV protection to determine its photoprotective potential.

3.6. Melanogenesis-Inhibitory Activity

Several studies have revealed that artocarpin inhibits melanin formation [40,42,44,46,87]. Regarding tyrosinase, the rate-limiting enzyme in eumelanin biosynthesis that converts tyrosine to DOPA and subsequently to dopaquinone, artocarpin did not show potent tyrosinase inhibitory activity using the dopachrome method with mushroom tyrosinase [43,46]. The IC₅₀ for tyrosinase inhibition of artocarpin isolated from wood blocks of Artocarpus was reported as >228 µM (99.5 µg/mL), whereas the IC₅₀ of kojic acid, a well-established skin-lightening agent, was 8.66 µM (1.23 µg/mL). Nevertheless, in vivo studies have demonstrated promising results. Artocarpin (purity not specified) at a concentration of 0.25 M (10.91% (w/v)) in propylene glycol and ethanol solution effectively reduced UVB-induced hyperpigmentation in guinea pigs [44]. Additionally, a study on UV-induced hyperpigmented dorsal skin of C57/BL6 mice demonstrated that Artocarpus heartwood extract containing approximately 45% (w/w) artocarpin formulated as a 0.02% (w/w) nanoemulsion significantly ameliorated hyperpigmentation [40]. The formulation vehicle appears to influence efficacy, as the nanoemulsion showed greater hyperpigmentation reduction compared to the propylene glycol and ethanol mixture. Furthermore, a clinical study confirmed the skin-lightening effect of artocarpin (approximately 89.5% purity) formulated in a hydrogel patch (artocarpin content: 0.07 mg/cm²) [87]. The formulated patch significantly improved hyperpigmented facial areas in subjects (n = 30) after three weeks of application compared to the control group (n = 29) who received patches without artocarpin. No adverse effects were observed. These findings strongly suggest that artocarpin holds considerable promise as a natural ingredient in dermatological formulations targeting hyperpigmentation disorders and as a skin-lightening agent in cosmetic applications. Based on these findings, it is reasonable to conclude that artocarpin likely inhibits melanogenesis through mechanisms distinct from direct tyrosinase inhibition.

The ability of artocarpin to attenuate the UV-induced production of free radicals and pro-inflammatory cytokines TNF-α and IL-6 in keratinocytes may contribute to its overall effects on pigmentation regulation, beyond its relative weak direct tyrosinase inhibition. The relationship between inflammatory cytokines and melanogenesis is complex and condition-dependent. While TNF-α has been reported to inhibit tyrosinase activity [32], UV-induced activation of the NF-κB pathway overall promotes melanogenesis by enhancing tyrosinase and PMEL expression in melanocytes [30,31]. Similarly, IL-6 exhibits dual roles in pigmentation, acting as a melanogenesis inhibitor in melanocytes while simultaneously promoting dendrite elongation and melanosome transfer, particularly in the age spot formation [30,31,33,34,35]. Thus, the anti-inflammatory action of artocarpin may modulate pigmentation not simply by blocking a single-pro-melanogenic signal, but by disrupting the broader inflammatory system that drives UV-induced pigmentation. By reducing oxidative stress, artocarpin may attenuate the feedback loop between inflammation and hyperpigmentation, in which paracrine mediators such as α-MSH, endothelin-1, and prostaglandins released from UV-damaged keratinocytes stimulate melanocytes and upregulate melanin production [34,36,37]. Furthermore, artocarpin may disrupt the prostaglandin E2 (PGE2) pathway, as inflammatory cytokine promotes PGE2 synthesis, in which turn stimulate melanogenesis [88,89]. By modulating inflammatory cytokine levels, artocarpin may also reduce post-inflammatory hyperpigmentation through attenuate of the p38, MAPk, and ERK signaling cascades involved in inflammation-induced pigmentary changes [90,91].

As all information mentioned above is based on available published data, the cellular mechanisms of artocarpin in skin photoprotection are summarized in Figure 3.

4. Integration of Artocarpin into Advanced Delivery Systems: Linking Biological Activities to Formulation Strategies

The preceding sections have established artocarpin as a multi-targeted bioactive compound with significant potential against UV-induced skin aging through its antioxidant, anti-inflammatory, anti-collagenase, anti-apoptotic, autophagy-modulating, and melanogenesis-inhibitory properties. However, the clinical translation of these promising biological activities is fundamentally constrained by the physicochemical limitations of artocarpin, particularly its poor water solubility (<0.1 mg/mL) and high lipophilicity (log P ≈ 5), which severely compromise its bioavailability and ability to penetrate the stratum corneum barrier.

The critical challenge in developing artocarpin-based cosmeceuticals lies in bridging this gap between demonstrated efficacy in cellular and animal models and practical application in topical formulations. This necessitates strategic selection and optimization of delivery systems that can overcome the formidable barrier properties of skin while maintaining stability and biological activity of artocarpin.

4.1. Rational Selection of Delivery Systems Based on Properties of Artocarpin

The choice of delivery system for artocarpin must account for several key considerations:

Lipophilicity and solubility profile: The high lipophilicity of artocarpin makes it an ideal candidate for lipid-based delivery systems, including liposomes, transfersomes, ethosomes, and lipid nanoparticles. These systems can accommodate artocarpin within their lipid domains, enhancing both solubility and stability.

Molecular size and structure: With a molecular weight of 436.5 g/mol and a prenylated flavonoid structure, artocarpin requires delivery systems that can facilitate penetration beyond the stratum corneum to reach target cells in the viable epidermis and dermis, where its biological activities are most relevant.

Target site of action: Given that artocarpin exerts its photoprotective effects primarily on keratinocytes and fibroblasts, the delivery system should optimize dermal retention rather than systemic absorption, making vesicular systems particularly appropriate.

Chemical stability: The phenolic hydroxyl groups in structure of artocarpin render it susceptible to oxidation. Encapsulation within protective lipid matrices or vesicular systems can shield these reactive groups from degradation.

4.2. Possible Delivery System for Artocarpin

Figure 4 illustrates the typical localization of a highly lipophilic active compound within the hydrophobic domains of a nanostructured lipid-based carrier, exemplified by a cubosome system. Although originally developed for cubosomes, this schematic highlights a general physicochemical principle that is relevant to other lipid-based systems reviewed here. Given the high lipophilicity of artocarpin, similar partitioning into lipid bilayers or lipid matrices can be anticipated for liposomes, transfersomes, ethosomes, and lipid nanoparticles.

4.2.1. Liposomes

Liposomes, a classical vesicular delivery system, are among the most extensively studied lipid–vesicular systems due to their biocompatibility, biodegradability, and structural similarity to biological membranes. Typically, liposomes are composed of phospholipids and often cholesterol to enhance membrane stability and fluidity [93,94]. Polyethylene glycol (PEG) is commonly added to improve circulation time, reduce opsonization, and increase stability [95,96]. These phospholipids self-assemble in aqueous media into bilayered vesicles, where hydrophilic head groups face the aqueous environment and hydrophobic tails form the inner bilayer. This structure enables dual substance-loading capabilities, in which hydrophilic substances reside in the aqueous core, while lipophilic substances are incorporated into the lipid bilayer [97]. For lipophilic substances, liposomes enhanced skin penetration of dl-α-tocopherol acetate [98], betamethasone [99], triamcinolone acetonide [100], and improved clinical efficacy of tretinoin in acne treatment [101]. For hydrophilic substances, they increased the dermal delivery of ascorbic acid [102] and glycolic acid in photodamaged skin [103]. These demonstrate the capacity of liposomes to enhance the penetration of both lipophilic and hydrophilic compounds. Variations in the polar head groups and nonpolar tails of phospholipids offer diverse options for vesicle formulation. Common types used in delivery systems, such as phosphatidic acids, phosphatidylglycerols, phosphatidylethanolamines, and phosphatidylcholines, influence key system properties including membrane fluidity, charge, and stability. The choice of phospholipid is typically based on the physicochemical characteristics of the delivered substance, the intended target tissue, and the route of administration. For instance, cationic phospholipids (e.g., DOTAP) are used for nucleic acid delivery to the lungs due to their ability to facilitate cellular uptake and complex formation [104,105], meanwhile neutral phospholipids like phosphatidylcholine (PC) are widely used in dermal applications due to their biocompatibility and ability to interact with the lipid structure of the stratum corneum [106]. This interaction can modify the lipid arrangement of the stratum corneum, enhancing liposome adhesion and retention on the skin surface. For example, liposomes containing soybean-derived PC (Phospholipon^® 80) showed uniform distribution within the stratum corneum lipid matrix, promoting interaction with skin lipids [107]. Such interactions increase the fluidity of the stratum corneum lipid bilayers, thereby enhancing active partitioning into the skin [108]. This effect was observed with fluid-phase lipids like EPC (egg phosphatidylcholine), but not with gel-phase lipids such as DSPC (distearoylphosphatidylcholine), highlighting the importance of phospholipid phase behavior in dermal delivery [108]. In vitro studies indicate that the structure and size of liposomes have minimal impact on the skin permeation of caffeine; instead, permeation increases with higher concentrations of soybean phosphatidylcholine, particularly those with unsaturated fatty acid chains, which enhance skin penetration [109]. Importantly, liposomes do not remain intact upon skin penetration. For instance, soybean PC liposomes disassemble within the epidermis and dermis, releasing encapsulated actives such as betamethasone, which then diffuses through the stratum corneum into deeper skin layers [99]. High-resolution stimulated emission depletion (STED) microscopy further confirmed that 100 nm liposomes are no longer detectable as intact vesicles beneath the skin surface [110]). Additionally, liposomes containing DPPG (dipalmitoyl phosphatidylglycerol) were shown to disrupt the stratum corneum lipid barrier, facilitating the delivery of both free and encapsulated caffeine [111]. These findings suggest that skin permeation enhancement is primarily driven by the phospholipid components acting as penetration enhancers, rather than by intact liposome vesicles.

4.2.2. Transfersomes

Transfersomes, also known as transferosomes, are ultra-deformable lipid vesicles composed of phospholipids and edge activators (typically single-chain surfactants) that have been designed to overcome the limitations of conventional liposomes in transdermal delivery due to the inability of liposome to pass through the narrow (≤30 nm) intercellular channels of the stratum corneum [112]. Unlike traditional liposomes, transfersomes incorporate surfactants that destabilize the lipid bilayer, imparting flexibility that allows the vesicles to squeeze through skin pores smaller than their own diameter [113]. Common edge activators (EAs) include sodium deoxycholate (SDS), Span 60, Span 80, Tween 60, and Tween 80 [113,114,115,116]. The type and phase of incorporation of EAs play a critical role in determining the physicochemical properties and performance of transfersomal formulations. For instance, SDS, an anionic surfactant, exhibited a significant impact on vesicle characteristics depending on the phase in which it was introduced during preparation. When SDS was added to the organic phase, it led to lower polydispersity index (PDI) values and a higher zeta potential, indicating more uniform and stable vesicles, likely due to improved integration of SDS into the phospholipid bilayer [116]. Moreover, an in vitro permeation study using Franz diffusion cells assessed the influence of different EAs, including Tween 80, Span 80, and SDC, on transfersomes composed of soybean lecithin, further incorporated into a gel base. Among these, Tween 80-based transfersomes achieved the highest percentage of asiatic acid permeation and flux through Strat-M^® membrane, a synthetic skin model, highlighting the importance of EA selection in optimizing dermal delivery [115]. A comparative study demonstrated transfersomes provided greater skin permeation than conventional liposomes in various substances and different models [117,118,119]. Transfersomes have been widely applied to enhance skin penetration and dermal delivery of various therapeutic agents. For example, curcumin, a lipophilic natural compound, when loaded in transfersomes containing Tween 80 or sodium cholate significantly increased its skin permeation and deposition [120,121]. Transfersomal phenylephrine HCl, a small hydrophilic compound, enabled enhanced deep dermal delivery with sustained release, achieving localized vasoconstriction [117]; while a large molecule of Panax notoginseng saponin, when loaded in transfersomes, could permeate through the skin and enter the blood rapidly [122]. Additionally, R-carvedilol-loaded transfersomes improved permeation and retention of the active ingredient in the skin, effectively reducing both acute UV-induced inflammation and chronic UV-induced carcinogenesis [123]. These findings suggest that transfersomes can effectively deliver both lipophilic and hydrophilic substances, regardless of molecular size, across the stratum corneum, making them a versatile system for enhanced transdermal delivery. Confocal Laser Scanning Microscopy (CLSM) imaging has confirmed the ability of transfersomes to penetrate deep into the skin. FITC-labeled transfersomes applied to mouse skin reached depths of ~100 µm, corresponding to the superficial dermis [124]. Similarly, triamcinolone acetonide-loaded transfersomes showed uniform distribution across the stratum corneum, epidermis, and dermis, with fluorescence detected up to 165 µm [125]. These findings demonstrate the potential of transfersomes to deliver substance beyond the stratum corneum into deeper, therapeutically relevant layers. One of the most widely accepted mechanisms explaining how transfersomes traverse the intact stratum corneum involves their migration through intercellular lipid domains, driven by a transcutaneous hydration gradient and aided by their high membrane deformability. This mechanism was originally proposed by [126], who introduced the concept of “osmotic force-driven transport”. The skin exhibits a hydration gradient, with low water content at the surface and higher hydration in the deeper viable epidermis. This gradient generates a thermodynamic (osmotic) pressure, which has been proposed to drive highly deformable vesicles, such as transfersomes, through the narrow intercellular lipid pathways of the stratum corneum despite their larger average size (typically 100–200 nm) [126,127]. Importantly, a non-occlusive application is essential to maintain this transepidermal osmotic gradient, which initiates and sustains vesicle movement across the skin barrier [128]. While the precise mechanism of their transport across the skin remains incompletely understood, multiple studies using Franz diffusion cells, fluorescence microscopy, and confocal imaging have confirmed their ability to improve the penetration and deposition of various substances. It remains a matter of scientific discussion whether transfersomes traverse the skin as intact vesicles or release their payload during passage. Nevertheless, their demonstrated capacity to overcome the stratum corneum barrier and deliver active compounds to deeper skin layers highlights their strong potential as effective transdermal carriers.

4.2.3. Ethosomes

Ethosomes are a modified liposomal system composed of soybean PC (Phospholipon 90), ethanol (20–30%), and water. Paramagnetic ion NMR studies confirmed that at these ethanol concentrations, phospholipids form closed bilayers with looser packing and increased membrane permeability to cations compared to conventional liposomes. Confocal Laser Scanning Microscopy (CLSM) revealed that ethosomes exhibit significantly higher fluorescence intensity and penetrate deeper into mouse skin, reaching depths of approximately 140 µm, unlike liposomes lacking ethanol [129]. Since their development, ethosomes have been extensively investigated for their ability to enhance transdermal delivery, not only of small lipophilic compounds [130,131], but also of macromolecules such as insulin [132]. Their enhanced skin permeation and biocompatibility have made ethosomes effective carriers for improving dermal and transdermal delivery of various therapeutics [133,134]. Compared to other vesicular systems such as liposomes, ethosomes contain a higher ethanol concentration, which acts as a potent penetration enhancer. This elevated ethanol level is believed to increases the fluidity of stratum corneum lipids, disrupting the lipid bilayer and reducing lipid density, thereby enhancing penetration of the interested substance into deeper skin layers [135]. The ethanol concentration plays a crucial role in the formulation and performance of ethosomal systems. An increase in ethanol content generally leads to a reduction in vesicle size, as demonstrated in formulations containing soybean phosphatidylcholine and yolk phospholipids [129,136]. However, this size reduction can be accompanied by trade-offs in other formulation aspects. At high ethanol levels (e.g., 40%), ethosomes formulated with unsaturated diacyl-phosphatidylcholine exhibited both a significant decrease in active entrapment efficiency and an unexpected increase in particle size, likely due to bilayer destabilization [137]. In contrast, moderate ethanol concentrations ranging from 25% to 35% have been shown to enhance transdermal permeation, particularly in systems using synthetic phospholipids such as 1,2-dimyristoyl-sn-glycero-3-ethyl-phosphatidylcholine (EDMPC) combined with unsaturated linoleic acid [132]. These observations underscore the importance of optimizing ethanol content in ethosomal formulations to achieve a favorable balance between vesicle size, encapsulation efficiency, and skin permeation.

New-generation ethosomes, known as binary or dual-alcohol ethosomes, have been developed by incorporating a second alcohol, typically propylene glycol (PG) or isopropyl alcohol (IPA), alongside ethanol. This dual-alcohol approach aims to enhances substance solubility, formulation stability, and skin penetration while potentially reducing ethanol content, making it more suitable for sensitive skin [138]. In a comparative study, binary ethosomes formulated with an ethanol-to-PG ratio of 7:3 demonstrated the highest cumulative permeation of terbinafine hydrochloride through mouse skin in vitro, outperforming both other ethanol and PG ratios and conventional ethosomes without PG [139]. The stabilizing effect of PG in binary ethosomes has been demonstrated through improved particle size and zeta potential stability under stress conditions such as high salt concentrations and extreme pH, which can disrupt the membrane structure of the ethosomal system. Additionally, PG helps maintain stability upon dilution, a common occurrence during the incorporation of ethosomes into cosmetic formulations [140]. PG likely enhances ethosome stability by increasing viscosity, reducing ethanol volatility, and inhibiting hydrolysis, thereby protecting the lipid bilayer structure. Additionally, binary ethosomes formulated with isopropyl alcohol as the second alcohol showed significantly greater ketoconazole release and skin permeation in ex vivo rat skin, while maintaining comparable entrapment efficiency and zeta potential to conventional ethosomes [137]. These findings highlight the potential of binary ethosomes as an advanced transdermal delivery system offering improved performance, stability, and adaptability for both pharmaceutical and cosmetic applications.

4.2.4. Lipid Nanoparticles

Lipid nanoparticles (LNPs) have gained significant attention as carriers for topical and transdermal delivery owing to their ability to solubilize and stabilize lipophilic substances, facilitate deeper skin penetration, and enable controlled or sustained release [141]. They were first introduced in the early 1990s, with a particle matrix composed of solid lipids that remain solid at body temperature, which distinguished them from nanoemulsions and fluid liposomes; hence, they were termed solid lipid nanoparticles (SLNs) [142]. To overcome limitations of SLNs, such as expulsion of the encapsulated substance caused by lipid crystallization and limited deformability, nanostructured lipid carriers (NLCs) were developed by incorporating a mixture of solid and liquid lipids, improving substance loading, stability, and penetration [143]. These colloidal systems are typically 50–1000 nm in size and consist of a biocompatible lipid matrix stabilized by a surfactant layer. The matrix may be composed of a single highly crystallized solid lipid or a mixture of lipids with different melting points, while the surfactant layer can include one or more emulsifiers and co-emulsifiers [144,145]. In terms of encapsulation, three theoretical models have been proposed for LNPs: (i) homogeneous matrix, (ii) active-enriched shell, and (iii) active-enriched core [146]. The model obtained depends largely on the solubility of the interested substance in the lipid, its concentration, and the production technique (e.g., hot or cold homogenization). These structural arrangements critically influence both the physical stability of the formulation and the release kinetics of the encapsulated compound [147].

Several studies have demonstrated the ability of LNPs for lipophilic antioxidants and anti-aging compounds. Curcumin SLNs hydrogel exhibited improved photostability and enhanced anti-inflammatory activity for wound healing compared to free curcumin [148]. Comparative studies showed that resveratrol-loaded NLCs achieved deeper skin penetration and stronger antioxidant effects than SLNs in ex vivo models [149]. However, recent advances in resveratrol-loaded SLNs preparation, such as high-shear Ultra-Turrax homogenization at 24,000 rpm with thermal processing, have yielded smaller, more stable particles with controlled and sustained skin permeation, narrowing the performance gap with NLCs [150]. Carotenoids including β-carotene, lycopene, and coenzyme Q10 have also been successfully encapsulated in LNPs, demonstrating enhanced chemical stability, improved skin absorption, and increased bioavailability [151]. Similarly, α-tocopherol incorporated into SLN-type carriers prepared with various hard fats and fully hydrogenated oils exhibited greater oxidative stability [152]. Retinol encapsulated in SLNs showed improved stability, reduced irritation, and higher dermal retention, supporting its value in anti-aging applications [153]. Beyond cosmetics, pioglitazone-loaded NLCs achieved a 2.17-fold increase in bioavailability via transdermal application compared to oral tablets, with prolonged hypoglycemic effects in vivo, highlighting the potential of LNPs for systemic delivery as a non-invasive alternative [154]. These findings underscore the versatility of LNPs in protecting unstable compounds, enhancing bioactivity, and broadening applications from skin care to systemic therapy.

While the exact mechanisms of nanoparticle penetration are not fully elucidated, LNPs are proposed to enhance skin permeation through multiple effects. These include strong adhesion to the skin, formation of an occlusive film on the stratum corneum, increased hydration, and fluidization of intercellular lipids, all of which contribute to improved diffusion of the encapsulated substance [155]. Comparative studies have shown that SLNs with an average size of ~200 nm significantly outperform lipid microparticles (~4 µm) in enhancing the occlusion factor, achieving values of approximately 50% versus 10% in in vitro water evaporation models. This effect is explained by the fusion model, where small SLNs coalesce under capillary forces to form a continuous, poreless film that reduces transepidermal water loss, unlike the loosely packed layers formed by larger microparticles [146,156]. Supporting these findings, a 4-week in vivo study in human volunteers demonstrated that an SLN-enriched o/w cream produced significantly greater skin hydration than a conventional cream (~31% vs. ~24%) [157]. In terms of penetration routes, LNPs can access the skin via intercellular, transcellular, and transappendageal pathways (through hair follicles and sweat glands); these routes vary depending on the nanoparticle size, composition, and target depth [158,159].

Despite their advantages, LNPs face limitations such as potential expulsion of the encapsulated substance, limited loading of the interested substance in SLNs, and restricted deformability that may hinder deeper skin penetration. To address these issues, advanced systems have been developed, including NLCs, polymer–lipid hybrid nanoparticles, ethosomes/nanostructured lipid carriers, and combinations of SLNs with microneedle patches, all of which have demonstrated improved loading, stability, and transdermal delivery performance of the interested actives [160,161,162]. Their safety profile is supported by the use of physiological lipids and generally recognized as safe (GRAS) surfactants, which resemble the natural lipid composition of skin and confer excellent compatibility with low toxicity [143,163].

Taken together, these mechanisms, penetration routes, and advancements underscore the versatility of LNPs as effective carriers for dermal and transdermal delivery, particularly for lipophilic antioxidants and anti-aging compounds, while highlighting areas for future research and optimization.

4.2.5. Comparative Overview of Lipid-Based Delivery Systems

Each of the lipid-based delivery systems discussed, including liposomes, transfersomes, ethosomes, and lipid nanoparticles, offers distinct advantages and faces unique challenges in dermal and transdermal drug delivery. While they share the common foundation of lipid-based architecture and biocompatibility, their structural differences result in varying penetration ability, loading efficiency, and stability. To improve clarity and facilitate direct comparison,

Table 1. Summary comparison of lipid-delivery systems for dermal and transdermal delivery.

Delivery Systems	Composition	Key Advantages	Main Limitations	Skin Penetration	Formulation Challenges	References
Liposomes	Phospholipids Cholesterol	Biocompatibility and biodegradable Dual loading (hydrophilic + lipophilic) PL act as penetration enhancers	Lack of elasticity Limited to upper skin layers Low stability and drug leakage	Disassemble in epidermis/dermis Disrupt SC facilitate actives delivery Actives diffuse to deeper layers	PL selection (based on actives) PL phase behavior and concentration optimization Storage stability	[93,94,97,108,111,164]
Transfersomes	Phospholipids Edge activators	Ultra-deformable structure Superior penetration vs. liposomes Versatile cargo (lipophilic, hydrophilic, macromolecules) Osmotic gradient-driven	Complex formulation Require non-occlusive application Performance dependent on edge activator	Depth 100–165 µm of mouse skin (CLSM) Reach superficial dermis Uniform SC, epidermis, dermis distribution	Edge activator Selection critical Phase of EA Incorporation Balancing flexibility vs. stability	[113,116,117,118,119,120,121,122,124,125,128]
Ethosomes (including Binary)	Phospholipids Ethanol Binary: + propylene glycol or isopropyl alcohol	Ethanol act as potent penetration enhancers Delivers small to macromolecules Binary: better stability, less irritation	High ethanol may irritate skin Excessive ethanol reduces entrapment Predisposition to oxidative degradation	Depth ~140 µm of mouse skin (CLSM) Deeper than conventional liposomes Ethanol increase SC fluidity	Optimizing ethanol% (25–35% optimal) Balancing size, entrapment, permeation Binary: alcohol ratio optimization needed	[129,130,131,132,135,136,137,138,139,140,164]
Lipid Nanoparticles (SLNs/NLCs)	SLNs: Solid lipids NLCs: Solid + liquid lipids Surfactants/co-emulsifiers	Controlled/sustained release High stability (solid matrix) Strong occlusion and skin hydration Multiple penetration routes	Potential actives expulsion (SLNs) Limited loading in SLNs Restricted deformability Size-dependent performance	Variable by size/composition NLCs > SLNs Intercellular, transcellular, follicular routes	Stability based on lipids selection Solid/liquid lipid ratio (NLCs) Production technique impact	[144,145,149,151,152,153,155,156,157,158,159]

Abbreviations: SC = Stratum Corneum; CLSM = Confocal Laser Scanning Microscopy; SLNs = Solid Lipid Nanoparticles; NLCs = Nanostructured Lipid Carriers; PL: Phospholipids; EA = Edge Activator.

summarizes the key characteristics of these four systems, including their composition, advantages, limitations, skin penetration, and major formulation challenges.

5. Conclusions: A Roadmap for Artocarpin Cosmeceutical Development

Artocarpin demonstrates multifunctional anti-photoaging properties through several mechanisms. It provides antioxidant protection via both direct radical scavenging and Nrf2-ARE pathway activation, thereby upregulating endogenous antioxidant defenses. Its anti-inflammatory effects against UV-induced inflammation target the NF-κB and MAPK pathways, based on current knowledge. The compound maintains collagen homeostasis by inhibiting MMP-1 mediated degradation while preserving collagen synthesis and fibroblast function, including α-SMA expression and mechanical properties. It also exhibits selective apoptosis modulation, being protective in normal cells but pro-apoptotic in damaged or abnormal cells, thereby supporting tissue homeostasis. Regarding melanogenesis-inhibitory activity, it occurs through anti-inflammatory mechanisms rather than direct tyrosinase inhibition, effectively addressing post-inflammatory hyperpigmentation. Additionally, artocarpin may modulate autophagy to facilitate the removal of damaged cellular components, but this requires further investigation. Overall, its multi-targeted approach addresses anti-photoaging through interconnected molecular mechanisms affecting oxidative stress, inflammation, ECM degradation, pigmentation, and cellular renewal.

Despite these promising biological activities, the skin permeation of artocarpin faces significant physicochemical challenges. The poor water solubility of the compound (<0.1 mg/mL) and high lipophilicity (log P ≈ 5) severely limit its ability to penetrate the stratum corneum barrier and diffuse into viable skin layers, which possess hydrophilic properties. Additionally, the phenolic hydroxyl groups in its structure renders it susceptible to oxidation, particularly in alkaline conditions. These factors are commonly encountered in cosmetics during manufacturing, storage, and use.

For development of topical artocarpin formulation, physicochemical stability is a primary consideration. Stability can be enhanced through incorporation of lipophilic antioxidants, such as α-tocopherol and butylated hydroxytoluene (BHT), along with light-protective packaging and careful pH control to prevent oxidative degradation of the phenolic hydroxyl groups. To address the skin penetration, lipid-based delivery systems represent a particularly suitable approach. Due to the lipophilic nature of these systems, artocarpin can be efficiently incorporated into their structures. This review highlights the promising potential of liposomes, transfersomes, ethosomes, and nanostructured lipid carriers (NLCs) for artocarpin transepidermal delivery. Although all these systems share a lipid-based composition, each enhances stratum corneum penetration through a distinct mechanism. The selection of an appropriate delivery system should therefore be guided by specific formulation objectives and target penetration depth.

Beyond penetration enhancement, the safety and tolerability profile of artocarpin within each delivery system warrants careful consideration and should be further investigated prior to commercial application. Furthermore, to broaden the photoprotective efficacy of artocarpin, co-encapsulation with other natural antioxidants may offer synergistic benefits by simultaneously targeting multiple mechanisms involved in UV-induced skin damage.