Nanocarriers Responsive to Light—A Review

Abstract

The non-specific and minimally selective nature of traditional drug administration methods, along with various other limitations, makes the use of drug delivery systems more favorable. Light-responsive, or light-triggered, drug delivery systems provide more controlled and less invasive treatment approaches, addressing the shortcomings of traditional methods. In this paper, we reviewed studies utilizing light-triggered nanoparticles (NPs) for treating cancer and various other diseases, focusing on photodynamic therapy (PDT) and photothermal therapy (PTT) in both in vivo and in vitro applications. Most of the reviewed studies employed synergistic approaches that combined PDT or PTT with other therapeutic methods to leverage the strengths of both techniques and enhance treatment efficiency or to overcome the individual limitations of each method, which is discussed extensively in this paper.

1. Introduction

Drugs can be administered to the body through multiple routes, such as enteral (oral, rectal), parenteral (intravenous and intramuscular, etc.). Then, the drug is absorbed, distributed, metabolized, and eventually eliminated. These processes play a crucial role in determining the drug’s effectiveness and safety, as they control how the drug reaches its target and how long it remains active in the body [1]. Drug delivery systems encompass various methods and approaches for delivering pharmaceutical compounds into the human body to achieve the desired therapeutic effects while minimizing, or ideally eliminating, the undesired effects and limitations of conventional drug administration methods, which are often non-specific and minimally selective. Conventional methods also face challenges such as rapid drug clearance and difficulty in passing biological barriers, which can reduce therapeutic efficacy and increase systemic toxicity, compromising treatment outcomes. These issues have led to the development of new, more effective drug delivery systems [2,3,4]. Drug delivery systems can also be classified based on different administration routes, including intravenous (IV) injections, oral administration, and other methods, all aimed at providing controlled and targeted release, improving solubility and bioavailability, reducing drug clearance time, and enhancing patient compliance [2]. Nanotechnology, particularly polymer nanoparticles, is being utilized to address the limitations of conventional delivery methods [3]. Light-responsive, or light-triggered, polymers are a specific type of polymer nanoparticle that alters their properties or behavior upon exposure to light, classifying them as exogenous stimuli-responsive materials [3]. Light-triggered drug delivery systems are extensively studied for cancer treatment to mitigate the drawbacks of traditional chemotherapy [5]. This review examines recent advancements in light-triggered drug delivery systems, focusing on photodynamic therapy (PDT) and photothermal therapy (PTT), as well as their synergies with other approaches for the treatment of cancer and other diseases.

2. Intrinsic Drug Delivery Systems

Non-conjugated luminescent polymers (NLPs) are considered intrinsic luminescent materials because they emit light without external excitation sources or any conjugated structures. NLPs offer promising prospects for drug delivery due to their heightened luminescence when aggregated, as well as their structural versatility and natural origin, which show their potential as biocompatible drug carriers; however, the utilization of NLPs as drug carriers has not been extensively studied, and only a few studies are exploring that [6,7,8].

Table 1. The advantages of using NLPs as drug carriers [6].

Advantages	Explanation
Luminescence	NLPs become highly luminescent when they aggregate, which allows for more effective monitoring and tracking of the drug in the body
Structural Versatility	The provided structuring flexibility and functional adaptation of NLPs to various applications facilitate their use as luminescent drug carriers
Natural Origin	NLPs, such as chitosan and sodium alginate, demonstrate high biocompatibility, making them promising candidates for drug delivery
High Biocompatibility	Chitosan, for instance, is degradable and is a cell adhesive, offering high biocompatibility

below lists the advantages of using NLPs as drug carriers.

3. Extrinsic Drug Delivery Systems

Extrinsic drug delivery systems are systems triggered by an external source, such as light, to release the carried drug. These systems offer many benefits, such as precision dosage delivery and controlled drug release at a specific target. However, there are drawbacks to using these systems as well. For example, light-triggered systems have limited tissue penetration depth, require high-energy light sources like lasers, and have sensitivity problems with particular light sources [9]. Moreover, the type of light used highly influences the system’s performance. For instance, continuous wave (CW) maintains a constant energy output, whereas ultrafast lasers emit brief and intense pulses, allowing for more precise control over the drug release [10].

Table 2. The pros and cons of using light-triggered drug delivery systems [9,10].

Aspect	Advantages	Disadvantages
Precise Drug Delivery	Enables precision of dosage and release timing	The complexity and cost associated with using high-energy light sources, such as lasers, and the limited sensitivity of some systems to less powerful light sources, like light-emitting diodes (LEDs), present significant challenges. Additionally, differences in responses between continuous wave (CW) and ultrafast laser irradiation may necessitate system-specific optimization
Non-Invasive	Offers non-invasive drug delivery methods, minimizing the risks of invasive delivery	Limited tissue penetration depth of light sources can restrict applications to superficial tissues
Remote Control & Spatiotemporal Resolution	Allows remote activation of drug release, providing flexibility. Provides high spatiotemporal resolution of drug delivery, enabling controlled and targeted therapy	Developing specialized delivery systems compatible with specific light wavelengths is required. Light parameters, including wavelength, pulse duration, and intensity, can significantly influence drug delivery outcomes

below summarizes some of the pros and cons of using light-triggered drug delivery systems.

4. Nanoparticles

Nanoparticles (NPs) are particles ranging in size from 1 to 100 nm and are utilized as drug delivery systems due to their efficiency, particularly in contemporary applications. Their small size and high volume-to-surface ratio contribute to their effectiveness. NPs can be broadly categorized into organic and inorganic materials. Organic nanoparticles, such as micelles, liposomes, and dendrimers, are known for their biocompatibility and biodegradability. In contrast, inorganic nanoparticles exhibit exceptional stability, high loading capacity, adjustable degradation rates, and various multifunctional properties, including thermal and optical characteristics. Common materials used in inorganic nanoparticles include graphene, iron oxide, zinc oxide, gold, and silver [11,12].

4.1. Organic Nanoparticles

Using organic NPs as nanocarriers in drug delivery offers several advantages, including high biocompatibility and biodegradability; however, organic nanoparticles also encounter challenges such as recognition by macrophages, rapid drug clearance from the body, complex synthesis processes, and variability in their properties [11]. Each type of organic nanoparticle has its own advantages and limitations that need to be considered when designing drug delivery systems.

Table 3. The advantages and limitations of the usage of some hybrid drug delivery systems.

NPs	Advantages	Disadvantages	Refs.
Liposomes	Highly biocompatible and biodegradable	Larger sizes (>100 nm) may be recognized by macrophages, leading to organ aggregation	[13]
	Can encapsulate both hydrophobic and hydrophilic drugs	Smaller sizes (<10 nm) are cleared rapidly from the body
	Lower cytotoxicity to healthy cells
Micelles	Structurally adaptable based on the application	Complex to form as they can only assemble above a certain critical micelle concentration	[11,14]
	High stability, can encapsulate hydrophobic molecules and bind antibodies on the surface
Polymeric Nanoparticles	Highly biocompatible and biodegradable	Potential toxicity if they are not adequately synthesized	[15]
	Versatile in size and structure, allowing surface modifications	Complex synthesis conditions
	Encapsulate both hydrophobic and hydrophilic drugs
Dendrimers	The size, shape, and surface functionalization can be precisely controlled	Synthesis can be complex and time-consuming	[11]
	Controlled and sustained release profiles	The complexity of the synthesis can result in differences in properties between different batches, which affects reproducibility
	The drug-loading capacity for pharmaceutical agents is high
Chitosan Nanoparticles	Approved by the FDA	May require surface modifications, adding complexity to synthesis	[11]
	Biocompatible and biodegradable
	Allow surface modifications

below provides an overview of these nanoparticles, listing their benefits and the challenges associated with their use.

Even though using organic NPs is promising for drug delivery, they face clinical limitations such as issues with scalability, clearance rates, and long-term safety. Liposomes, for instance, may either rapidly clear or accumulate in the organs depending on their size, which reduces their effectiveness. Dendrimers suffer from complex synthesis processes and conditions. Chitosan nanoparticles require surface modifications that complicate production. Micelles, while good at encapsulating drugs, can have inconsistent release profiles. Thus, more research into the biodegradability and safety of these organic NPs is needed to ensure their efficiency in clinical therapies.

Polymeric Nanoparticles

Polymeric nanoparticles have recently garnered significant attention due to their stability, ability to encapsulate a wide variety of drugs while protecting them from degradation, and small sizes ranging from 1 to 1000 nm. However, the primary concern with polymeric nanoparticles is their potential toxicity. They can be categorized into nanocapsules and nanospheres, each with distinct structures and applications. Figure 1 below demonstrates the structural differences between nanocapsules and nanospheres.

Table 4. Comparison between Nanocapsules and Nanospheres [16].

Aspect	Nanocapsules	Nanospheres
Structure	Oily core surrounded by a polymeric shell	Continuous polymeric network
Drug Encapsulation	The drug dissolved in the oily core	Drugs can be retained inside or adsorbed onto the surface

illustrates the structural differences between nanocapsules and nanospheres and the locations of drug encapsulation within these nanoparticles [16].

Table 5. Different types of drugs can be encapsulated in nanocapsules and nanospheres and their applications [16].

Formulated Drug/Bioactive	Type of Polymeric Nanoparticles	Application	Refs.
Coumarin-6 (C-6)	Nanospheres	Used for bioimaging and drug delivery	[17]
Rapamycin	Nanospheres	Exhibits anti-glioma activity	[18]
Hyperforin	Nanospheres	Provides anti-inflammatory effects	[19]
Fenofibrate (Feno)	Nanospheres	Targets ocular neovascularization	[20]
Amphotericin B (Amp B)	Nanocapsules	Treats Leishmania and fungal infections	[21]
Fenofibrate (FF)	Nanocapsules	Designed for oral delivery applications	[22]

shows the different types of drugs which can be encapsulated in both nanocapsules and nanospheres [16].

4.2. Inorganic Nanoparticles

Inorganic NPs, such as gold nanoparticles (AuNPs), silver nanoparticles (AgNPs), copper nanoparticles (CuNPs), and copper oxide nanoparticles (CuONPs), as well as many other metal and metal oxide NPs such as iron and zinc and their oxides, offer unique advantages for drug delivery applications due to their optical, magnetic, and structural properties. These NPs can be modified to suit specific applications in PDT, PTT, and imaging [23,24,25]. The use of inorganic NPs is highly affected by toxicity concerns, mainly due to metal ion release and the generation of ROS, which can cause oxidative stress, cellular damage, and death [23,24]. Surface modifications have been used to mitigate toxicity risks to alter the physical and chemical properties of NPs by allowing for reduced production of ROS and further enhancing biocompatibility [26,27]. Other approaches to mitigate toxicity include conjugating NPs with antibodies, coating modifications, and morphology and size modifications [24].

Inorganic nanoparticles are promising for drug delivery systems, providing unique advantages and addressing specific challenges.

Table 6. Advantages and disadvantages of inorganic nanoparticles.

Advantages	Disadvantages
High stability in comparison with organic nanoparticles [12]	They often exhibit toxicity due to metal ion release or reactive oxygen species generation, but surface modifications such as polymer coating or biocompatible ligands have been employed to mitigate these effects [23,24,26]
2. It can be locally delivered, and the surface can be modified, which reduces cytotoxicity [12,26]
3. Modification capability with ligands to improve efficiency and targeting [12,24]	2. Complex modification processes [24]
4. A wide range of properties which makes them suitable for various applications [12]

summarizes the advantages and disadvantages of inorganic nanoparticles, emphasizing their benefits compared to organic nanoparticles and listing some of their limitations.

5. PDT in Drug Delivery

PDT is a non-invasive mechanism where photosensitizing agents (PSs) are excited using wavelength-specific light. This will chemically produce highly reactive oxygen species (ROS) from the oxygen in the tissues and selectively kill the targeted cells, such as tumor cells and nearby blood vessels [28,29]. PDT is effective in treating cancer and various other diseases [29]. Photodynamic therapy (PDT) involves two main steps: first, the administration of a photosensitizer, which selectively accumulates in target cells; second, the activation of the photosensitizer using light, resulting in the generation of reactive oxygen species (ROS) that destroy the targeted cells [29]. Some limitations of PDT include the high dependence on oxygen, the limited penetration depth of the light, and the inability to apply on the whole body in cases where the cancer stage is advanced or when its size is quite large [29,30]. Figure 2 below demonstrates the mechanism of PDT.

In their recent study, Zhang et al. [31] introduced a novel photo-responsive drug delivery system called TPNPs-HA. This system was designed to deliver tirapazamine (TPZ) specifically to activated M1-type macrophages. These macrophages produce inflammatory factors that contribute to the progression of the autoimmune disease rheumatoid arthritis (RA). The system is based on a metal–organic framework constructed with porphyrin, a photosensitizer. Porphyrin generates reactive oxygen species (ROS) upon exposure to near-infrared (NIR) light. TPZ is a hypoxia-activated prodrug with chemotherapeutic properties, which are triggered by a hypoxic environment. The combination of these two approaches creates a synergistic effect that enhances the inhibition of macrophage activity [31].

Enzian et al. [32] studied light-triggered targeted drug delivery utilizing longer wavelengths ranging from 650 to 800 nm. This approach allows for deeper tissue penetration, facilitating drug delivery to deeper sites within the tissue [13]. They synthesized liposomes encapsulating the amphiphilic porphyrin and its derivatives, chlorin, and bacteriochlorin. The findings revealed that at 650 nm, chlorin facilitated over 75% drug release, while at 740 nm, bacteriochlorin achieved more than 60% release. These results highlight the potential for targeted drug distribution in deeper tissues [32].

In the study by Ali et al. [33], near-infrared (NIR) light-triggered hydrogels were developed specifically for anticancer therapy. These hydrogels were created using thioketal cross-linkers, which cleave in response to reactive oxygen species (ROS) produced by near-infrared (NIR)-excited indocyanine green (ICG). The cross-linkers were combined with carboxymethyl cellulose to form a porous structure through a bio-orthogonal reaction. Both the chemotherapy drug doxorubicin (DOX) and the NIR dye indocyanine green (ICG) were encapsulated within these hydrogels. Upon NIR light application, 96% of DOX was released as the ROS cleaved the thioketal bonds; in contrast, the release was minimal without NIR light. Furthermore, in vitro experiments demonstrated that the hydrogels were compatible with healthy cells, and the anticancer activity increased with exposure to NIR light [33].

Zhang et al. [34] present an overview of the concept of innovative ruthenium (Ru) nanophotocages, which are responsive to red or near-infrared (NIR) light, as a controlled drug delivery method for cancer therapy. Using photoactivated chemotherapy (PACT), these nanophotocages release therapeutic agents once exposed to near-infrared (NIR) light, enhancing treatment efficacy. This study shows the potential of Ru nanophotocages in drug-delivery systems [34].

In [35], Zhang et al. developed a synergistic approach of light-triggered liposomes loaded with DOX and Ce6 to treat cervical cancer. These liposomes were synthesized via the thin film hydration method, and they enhance the concentration of the drug on the tumor site and reduce the toxicity in the surrounding tissue. Ce6 causes the generation of ROS when a 660 nm near-infrared (NIR) laser is applied, which ruptures the liposomes and releases Ce6 and DOX. As a result of this synergy between PDT and chemotherapy, there was a tumor growth inhibition of 71.90 ± 3.14%, which shows the potential of this approach in drug delivery [35].

Another synergistic approach in order to address a limitation of PDT, which is the limited production of singlet oxygen in the environment of the tumor as it is hypoxic, is what was done by Yin et al. [36]. They combined photosynthetic bacteria with a photothermal agent (gold nanoparticles) and a photosensitizer (chlorin e6). This has increased the efficacy of therapy and tumor oxygenation because of the photosynthetic bacteria’s ability to generate oxygen under near-infrared (NIR) light, ultimately improving oxygen conversion to singlet oxygen. Moreover, they used PTT in this study to enhance the therapy [36]. PTT will be discussed in the next section of this paper.

Guo et al. [37] addressed the issue of penetration depth, which PDT suffers from, by using Cerenkov luminescence (CL) to create an internal light source from radioisotopes that are decaying. Their novel approach showed that the Ce6 and the tumor-avid radiotracer are successfully delivered by goat milk-derived extracellular vesicles (GEV). In their in vivo experiments, this synergistic combination resulted in a 58.02% tumor inhibition rate and improved survival in treated mice [37].

Du et al. [38] adopted a synergistic approach, combining multiple methods to develop an injectable multifunctional hydrogel. This hydrogel addresses challenges in photodynamic therapy (PDT) for wound treatment, particularly those posed by biofilms and hypoxic environments. Their platform, triggered by near-infrared (NIR) light, was created by loading sodium nitroprusside into a porphyrin metal–organic framework (MOF) modified with platinum. This platform enhances PDT and improves treatment efficacy in oxygen-poor environments by converting hydrogen peroxide into oxygen. When NIR light is applied, the hydrogel generates heat, reactive oxygen species (ROS), and nitric oxide, breaking down biofilms and reducing bacterial populations in wounds [38].

Jin et al. [39] combined the use of liposomes for delivering the anticancer agent Ansamitocin P-3 (AP-3) with photodynamic therapy (PDT). They employed a microfluidic swirl mixer to create temperature-sensitive liposomes (TSLs) and encapsulate AP-3, addressing its low solubility. These TSLs can be triggered by near-infrared (NIR) light to release AP-3. Their in vitro and in vivo studies demonstrated that this formulation inhibits breast cancer growth while minimizing potential damage to surrounding tissues [39].

6. PTT in Drug Delivery

In photothermal therapy (PTT), the primary mechanism involves converting absorbed light into heat using photothermal agents (PTAs), which can be selectively applied in various medical treatments, including cancer. Unlike photodynamic therapy (PDT), PTT does not rely on oxygen to destroy tumor cells at the targeted site [40,41,42]. Near-infrared (NIR) light penetrates tissue more deeply than visible light and can stimulate photothermal agents (PTAs) to convert this energy into heat. The generated heat then induces thermal damage to tumor cells [40,41]. Figure 3 demonstrates the mechanism of PTT.

In their study, Hassani et al. [43] developed a temperature-sensitive, near-infrared (NIR) light-triggered polymer coated with tungsten nanosheets for photothermal therapy (PTT) and the delivery of letrozole. They optimized specific characteristics, such as surface morphology and thermal behavior. Factors like pH and temperature influenced drug adsorption; under more acidic conditions and NIR light exposure, letrozole release was significantly enhanced, following a non-Fickian diffusion mechanism as described by the Korsmeyer–Peppas model [43].

Chen et al. [44] addressed the challenge of immunosuppressive environments that limit immunotherapy efficacy. They developed a liposome loaded with a photothermal agent (PTA) called IR808 and the TLR7 agonist loxoribine prodrug. Near-infrared (NIR) light enhanced photothermal therapy (PTT) by directly killing tumor cells and releasing tumor antigens. These tumor antigens, along with loxoribine, counteract the effects of the immunosuppressive environment, stimulating the activation of antigen-presenting cells and enhancing T-cell responses, effectively acting as an in situ cancer vaccine. Furthermore, when combined with immune checkpoint blockade, this treatment not only destroys the primary tumor but also helps prevent the growth of secondary tumors [44].

Kuroki et al. [45] used micro- and nanosized water bubbles to explore an additive-free technique for enhancing light-triggered hydrogels’ volume phase transition rate (PNIPAM-co-AAc). Their results showed that increasing the standing time of the bubbles improved the transition rate by over 100 times. The bubbles act as efficient water channels, significantly enhancing the hydrogels’ response rates, as confirmed through dynamic light scattering and scanning electron microscopy characterization [45].

Another study by Hu et al. [46] presented a strategy to address the limitations of photothermal therapy (PTT) in breast cancer treatment, including the low accumulation of photothermal agents (PTAs) and a weak immune response. They developed a near-infrared (NIR)-triggered drug delivery system using hollow copper sulfide nanoparticles modified with hyaluronic acid (HA) and loaded with diethyldithiocarbamate (DDTC). Their results showed that, when combined with losartan, this system enhanced drug accumulation and penetration. Additionally, NIR light activation improved PTT by releasing Cu(DDTC)₂, which induced immunogenic cell death (ICD) and promoted T-cell infiltration [46].

Abdolyousefi et al. [47] combined photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy to treat melanoma. They developed unique nanoparticles (NPs) made of black titanium dioxide (b-TiO₂), known for its UV light responsiveness, and coated them with a molecularly imprinted polymer (MIP) to make them responsive to pH and temperature changes. By converting regular white TiO₂ into b-TiO₂, they enhanced its effectiveness. The MIP was designed to mimic the drug 5-Fluorouracil (5-FU), and their findings showed that the coated NPs absorbed more drug than uncoated NPs, released the drug efficiently in acidic, warm tumor-like environments, and supported PTT/PDT while delivering the drug [47].

Mimicking the retractability of the tentacles of Actinia, Yang et al. [48] designed a DNA nanocarrier to enhance the efficiency of photothermal therapy (PTT) and drug delivery. This system combines gold nanoparticles (AuNPs) with collapsible DNA structures that bind and release quercetin, an anticancer drug. When exposed to 800 nm light, the AuNPs generate heat, causing the DNA structure to unravel and release quercetin. Upon release, quercetin inhibits a protein that confers heat resistance to the tumor, ultimately improving PTT effectiveness [48].

Huang et al. [49] conducted a study focused on uveal melanoma (UM), the most common eye cancer in adults, which can lead to blindness. They developed iron(III)-tannic acid (Fe³⁺-TA)-coated nanoparticles (NPs) that combine chlorin e6 (Ce6) and poly(lactic-co-glycolic acid) (PLGA). These NPs provide a synergistic effect between photothermal therapy (PTT) and photodynamic therapy (PDT), enhancing treatment efficacy and inducing cell death by targeting the mitochondria of cancerous cells. Additionally, these NPs can be utilized in MRI and photoacoustic imaging for guided cancer treatment [49].

One significant limitation of photothermal therapy (PTT) is the heat tolerance of cancerous cells, primarily due to heat shock proteins (HSPs) that promote the formation of stress granules (SGs), enabling cancer cells to survive under various stress conditions. Tong et al. [50] sought to inhibit SGs to enhance PTT by developing PEGylated hollow copper sulfide (HCuS) nanoparticles (NPs) loaded with ISRIB, a drug that inhibits SGs. Their system employs lauric acid for controlled drug release, specifically targeting acidic tumor environments. Additionally, the application of near-infrared (NIR) light activates the HCuS NPs to release ISRIB, increasing tumor cell sensitivity to PTT and promoting immunogenic cell death (ICD). This approach also helps generate reactive oxygen species (ROS) in tumor-associated macrophages (TAMs), transforming them into a more active M1 state and improving the tumor microenvironment [50].

Curcumin (Cur) is an anticancer agent often used with erlotinib (Er) to enhance treatment efficacy. Chen et al. [51] developed a targeted drug delivery system to address the limitations of both drugs, including their low solubility in water and inability to specifically target cancer cells. This system is based on molybdenum disulfide (MoS₂) modified with polyethylene glycol (PEG) and biotin, and it is loaded with both Cur and Er. The system utilizes near-infrared (NIR) light to generate heat, facilitating the precise release of the drugs to target cancer cells. This synergistic approach, combining chemotherapy and photothermal therapy (PTT), successfully reduced lung cancer growth in their laboratory tests [51].

In their study, Yan et al. [52] aimed to overcome the limitations of nanoparticles (NPs) in delivering chemotherapy for triple-negative breast cancer (TNBC), such as difficulties in penetrating dense tumor tissue and low efficiency in reaching cancer cells. They developed nanorobots with a specialized head and tail design that enables them to navigate through blood vessels and penetrate deep into tumors, where near-infrared (NIR) light can be applied for drug release. Their results demonstrated that this nanorobotic system, in combination with NIR-triggered release and photothermal therapy (PTT), significantly reduced tumor growth in both TNBC bone metastasis models and other tumor types [52].

7. In Vitro Applications of Light-Triggered Drug Delivery Systems

This section reviews the in vitro applications of light-triggered drug delivery systems. Numerous studies in the literature focus on in vitro applications due to their lower complexity compared to in vivo applications [53].

Anderski et al. [54] developed near-infrared (NIR)-triggered nanoparticles (NPs) by incorporating light-triggered polycarbonates (LrPC) or PEGylated LrPC (LrPC-PEG) with PLGA, loading them with the photosensitizer mTHPC for photodynamic therapy (PDT) drug delivery applications. Their in vitro evaluations demonstrated controlled degradation of the NPs upon NIR light exposure, in contrast to the PLGA-only NPs, which remained intact. This study highlights the potential for safer, more controlled treatments using NIR-triggered NPs [54].

Yardley et al. [55] designed amphiphilic polymer nanoparticles (NPs) that respond to both UV light and temperature changes. These NPs consist of two components: a hydrophobic self-immolative polymer (SIP) block and a hydrophilic poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) block, with a UV-triggered linkage between them. They investigated how the collapse of PDMAEMA above its lower critical solution temperature (LCST) affects SIP depolymerization. Their findings indicated that while UV light triggered depolymerization at temperatures below the LCST, heating the system above 65 °C resulted in faster degradation of the NPs. This degradation was primarily driven by temperature rather than the UV-triggered linkage, suggesting the potential for depolymerization based on multiple stimuli [55].

Mahlert et al. [56] conducted a study on the in vitro applications of photodynamic therapy (PDT) for treating gastrointestinal tumors. They developed nanoparticles (NPs) from light-triggered polycarbonates (LrPC) and PLGA, loading them with the photosensitizer mTHPC. To enhance the mucus penetration ability of these NPs, they were also PEGylated. Their in vitro evaluations demonstrated improved cancer cell death, as evidenced by DNA damage and reduced cell viability tests [56].

Yuan et al. [57] developed a novel dendrimer-based star-shaped copolymer that is both light- and pH-responsive with amphiphilic properties. These copolymers self-assemble into micelles when placed in water, and their amphiphilic characteristics are derived from the spiropyran (SP) groups, which respond differently to each stimulus, allowing for precise control over the release of the encapsulated doxorubicin (DOX). The micelles demonstrated high biocompatibility, making them an excellent carrier for hydrophobic drugs [57].

Ji et al. [58] developed a nanocomposite for cancer treatment and imaging purposes. Their nanocarrier was constructed by applying amphiphilic copolymers derived from coumarin-based polymers onto hollow mesoporous silica nanoparticles (HMS@C18). Additionally, they modified the nanocarrier with folic acid to target tumor cells. When exposed to 800 nm NIR light, the copolymers degraded, releasing the encapsulated drug and demonstrating controlled drug release. The advantages of their system include a high drug-loading capacity and selectivity [58].

Croissant et al. [59] developed a novel approach for targeting cancer cells through a drug delivery system that responds to two-photon activation. The system was created using mesoporous organosilica nanocarriers (M2PS) equipped with disulfide nanogates. These nanoparticles, synthesized via co-condensation with a two-photon electron donor, enabled controlled drug release upon one- or two-photon excitation. In vitro tests conducted in aqueous solutions demonstrated effective drug release and successful targeting of cancer cells [59].

Yuan et al. [60] developed NIR light-triggered NPs for cancer therapy that encapsulate DOX and a conjugated polymer (CP), focusing on the synergy between PTT and chemotherapy. These NPs are designed to target cancer cells that overexpress a specific protein (integrin αvβ3) by adding a tripeptide called cRGD on their surface. Their in vitro results demonstrate the strong effect of this synergy as it shows a much lower IC50 of 13.7 μg mL⁻¹ than using each treatment alone, making it very effective for cancer therapy [60].

He et al. [61] developed a drug delivery system utilizing upconverting nanoparticles (UCNPs) coated with mesoporous silica and loaded with DOX. The release mechanism involved grafted ruthenium complexes on the nanoparticles, which function as gates (valves) that allow the release of DOX upon exposure to NIR light. In their design, the release occurs at low NIR light intensities, protecting the samples from damage. This low-intensity approach makes it suitable for various biomedical applications requiring controlled drug release [61].

Liu et al. [62] conducted another study focused on a novel valve system to enhance drug release mechanisms. They created a nano valve on mesoporous silica-coated UCNPs by modifying the surface with pyrene methyl ester (Py) molecules, which, along with β-cyclodextrin (β-CD), block the nanopores to retain the loaded drug. Upon applying NIR light, the UCNPs convert it to UV light, which cleaves the Py and releases the β-CD, facilitating the release of the encapsulated drug. Additionally, they linked β-CD to fluorescein isothiocyanate (FITC) to monitor drug release through luminescence resonance energy transfer (LRET). Their in vitro tests demonstrated high cytotoxicity against HeLa cancer cells, highlighting the potential of this system as an effective drug delivery mechanism [62].

Fomina et al. [63] introduced a polymeric material that degrades in response to low-power NIR light, which can penetrate deeply into tissues. The absorption of applied NIR light induces polymer breakdown through two-photon absorption. Even after a short exposure to low-power NIR or UV light, the polymer loses half of its molecular weight. Notably, it remains biocompatible both before and after disassembly, highlighting its potential for in vivo medical applications [63].

8. In Vivo Applications of Light-Triggered Drug Delivery Systems

This section reviews studies with in vivo applications of light-triggered systems from drug delivery.

Zhao et al. [64] were the first to explore NIR light-triggered drug delivery in live tumor tissues, as detailed in their study. Their design featured a yolk-shell nanocage system, which incorporated a mesoporous silica shell surrounding a UCNP core with the drug chlorambucil encapsulated. Upon application of 980 nm NIR light, the system triggered the release of the encapsulated chlorambucil, demonstrating an effective and controlled release mechanism [64].

Zhang et al. [65] developed a novel system to address two limitations of traditional light-triggered systems: the low depth of penetration and the harmful effects of UV and visible light on surrounding tissues. This system utilized upconverting nanoparticles (UCNPs), which convert NIR light into UV-visible light, thereby minimizing UV exposure to healthy tissues by confining the conversion to the nanoparticle–drug complex. Integrating these UCNPs with doxorubicin (DOX) into a photo-responsive copolymer created NIR-triggered nanocomposites capable of controlled drug release. Their in vitro results demonstrated efficient drug release and high cytotoxicity under NIR light, while in vivo studies confirmed enhanced antitumor efficacy with minimal side effects [65].

In many studies, PEGylation has been employed to enhance the stability and circulation of nanoparticles (NPs). However, the increased size also reduces the tumor penetration ability of these NPs. To overcome this limitation, Zhao et al. [47] proposed a light-triggered PEGylation/dePEGylation strategy. They developed NPs that respond to both NIR light and changes in pH, utilizing upconverting nanoparticles (UCNPs) to convert NIR light into UV-visible light, which subsequently removes the protective PEG layer. This removal activates the iRGD peptide, enhancing tumor targeting and facilitating deeper drug penetration into the tumor [66].

Zhao et al. [67] developed NIR-triggered nanocapsules composed of azobenzene polymers and up/downconversion nanoparticles (U/DCNPs). These nanocapsules have a size of approximately 180 nm and convert NIR light into UV/visible light, causing them to break down into smaller particles around 20 nm in size. Their in vivo results demonstrate that this approach allows for efficient accumulation in the tumor, rapid elimination from the tumor site, and controlled drug release for chemotherapy [67].

Xu et al. [68] focused on enhancing chemotherapy using the drug cisplatin by creating charge-convertible nanoparticles (NPs) made of Pt(IV)-loaded upconversion nanoparticles (UCNPs) coated with PEG-PAH-DMMA, which respond to the acidity of the tumor environment. The UCNPs convert the applied NIR light into UV light, activating Pt(IV) into Pt(II), which exhibits cytotoxic effects. This approach enhances drug release and cellular uptake while also facilitating imaging applications due to the upconversion luminescence (UCL) [68].

Su et al. [69] developed a microneedle patch that responds to NIR light for the treatment of wound biofilms. The patch is loaded with an antimicrobial peptide, W379, and a photothermal agent, IR780, and is coated with 1-tetradecanol (TD), a phase change material. Upon application of NIR light, IR780 generates heat, causing the TD coating to melt and release the peptide. This approach enhances antibacterial effectiveness and demonstrates strong antibiofilm activity in both in vivo and in vitro settings, with the potential to deliver other antimicrobial agents as well [69].

9. Discussion and Analysis

Using light-triggered materials to develop drug delivery systems is a well-researched approach to overcoming the limitations of traditional drug administration methods. This paper reviews studies utilizing photodynamic therapy (PDT) and photothermal therapy (PTT), as well as both in vivo and in vitro applications, to highlight the potential of light-triggered drug delivery systems. The development of innovative drug delivery systems addresses the significant challenges of conventional (traditional) drug delivery systems, including systemic toxicity, poor bioavailability, and lack of targeted delivery. Ligh-triggered drug delivery systems utilize the light’s ability to penetrate tissues to provide external control of drug release, which offers promising solutions for precision medicine.

Unlike traditional drug delivery approaches with non-specific biodistribution and low selectivity [2,3,4], light-triggered systems enable the targeted release of therapeutic agents with high spatiotemporal precision. Another advantage of light-triggered systems is the potential for creating patient-specific treatments, where the wavelength and intensity of light used can be tailored and customized to individual tissue characteristics, enhancing treatment efficacy while minimizing off-target effects.

Recent advancements in photodynamic therapy (PDT) and photothermal therapy (PTT) demonstrate significant potential in precision medicine. PDT relies on photosensitizing agents activated by specific light wavelengths to induce cell damage through reactive oxygen species (ROS), making it effective for various diseases, including cancer [28,29]. In contrast, PTT employs photothermal agents (PTAs) to convert absorbed light into heat without generating ROS [40,41,42]. While PDT relies on the generation of ROS, making it oxygen-dependent, the mechanism of PTT, thermal ablation, is oxygen-independent. This distinction allows their combination to effectively target hypoxic regions, a common feature in aggressive tumors. These synergistic strategies can overcome limitations unique to each therapy, allowing for more comprehensive treatment options. Most of the studies reviewed focus on combining PDT and PTT with other approaches to optimize treatment outcomes and address specific limitations inherent in each therapy, such as the reliance on oxygen levels in PDT and potential oxidative damage to surrounding tissues in both PDT and PTT. The synergy of these therapies with nanocarriers, smart hydrogels, and other responsive systems addresses these challenges, providing a more controlled and effective drug release mechanism. For instance, the integration of PDT and PTT with nanoparticles can enhance drug stability, improve bioavailability, and facilitate controlled drug release in response to light exposure. Moreover, light-triggered systems offer a minimally invasive approach with reduced toxicity, and the reviewed studies indicate that these systems can overcome challenges related to tissue penetration and intracellular delivery, which are often limitations of traditional methods. However, clinical challenges remain, including limited light penetration in deeper tissues and concerns regarding nanoparticle biocompatibility and long-term effects, which require further investigation. The transition from research to clinical application creates several challenges. Regulatory approval for nanomaterials is a significant issue, mainly due to their toxicity and long-term safety concerns. In addition, it is essential to develop nanocarrier systems that are scalable, reproducible, and cost-effective to ensure their widespread use in medical treatments [70].

9.1. PDT & PTT: Materials, Design, and Applications

The reviewed studies in this paper used various light-triggered materials in their designs for diverse applications.

Table 7. Summary of light-triggered materials utilized in the reviewed studies involving both photodynamic therapy (PDT) and photothermal therapy (PTT), including the specific applications of each study.

Type	Materials & Design	Disease/Application	Refs.
Photodynamic Therapy (PDT)	TPNPs-HA (MOF with porphyrin and TPZ)	Treatment of RA	[31]
	Liposomes encapsulating chlorin and bacteriochlorin	Targeted drug delivery to deeper tissue	[32]
	NIR light-triggered hydrogels with thioketal cross-linkers, Doxorubicin (DOX), and NIR-excited indocyanine green (ICG)	Cancer therapy	[33]
	Ruthenium (Ru) nanophotocages	Cancer therapy	[34]
	light-triggered liposomes loaded with DOX and Ce6	Cervical cancer therapy	[35]
	Photosynthetic bacteria with Au NPs	Cancer therapy (enhanced tumor oxygenation)	[36]
	Goat milk-derived extracellular vesicles (GEV) delivering Ce6 and tumor-avid radiotracer	Cancer therapy (tumor inhibition)	[37]
	Injectable hydrogel with sodium nitroprusside and porphyrin MOF modified with platinum	Wound treatment	[38]
	temperature-sensitive liposomes (TSLs) loaded with AP-3	Breast cancer treatment	[39]
Photothermal Therapy (PTT)	NIR light-triggered polymer coated with tungsten nanosheets	Breast cancer (PTT and letrozole delivery)	[43]
	Liposomes loaded with IR808 and loxoribine prodrug	Cancer immunotherapy (in situ cancer vaccine)	[44]
	Light-triggered hydrogels (PNIPAM-co-AAc) with water micro and nanobubbles	PTT (improved hydrogel response rates)	[45]
	NIR-triggered hollow copper sulfide nanoparticles (HA-modified, loaded with DDTC)	Breast cancer (PTT and immune response enhancement)	[46]
	Black titanium dioxide (b-TiO2) NPs coated with molecularly imprinted polymer	Melanoma (PDT/PTT and chemotherapy with 5-FU)	[47]
	DNA nanocarrier with Au NPs and quercetin	Cancer therapy (enhanced PTT and drug delivery)	[48]
	Fe III-TA-coated nanoparticles with Ce6 and PLGA	Uveal melanoma (synergistic PTT/PDT)	[49]
	PEGylated hollow copper sulfide nanoparticles loaded with ISRIB	Cancer therapy (overcoming heat tolerance and enhancing PTT)	[50]
	MoS2 modified with PEG and biotin, loaded with Cur and Er	Lung cancer treatment (synergistic chemotherapy and PTT)	[51]
	Nanorobots with head-tail design for NIR-triggered drug release	TNBC	[52]

below provides a comprehensive overview of the light-triggered materials utilized in photodynamic therapy (PDT) and photothermal therapy (PTT), systems, along with the specific applications of each study.

The materials summarized in Table 7 demonstrate the diversity of light-triggered platforms utilized in PDT and PTT. These approaches underscore the versatility of light-triggered systems in addressing complex medical conditions, particularly cancer.

9.2. Applications and Used Materials in the Reviewed In Vivo and In Vitro Studies

This section summarizes the light-triggered materials used in the reviewed in vivo and in vitro studies.

Table 8. Summary of the reviewed in vivo/in vitro studies showing the design and application of each study.

Type	Materials & Design	Type of Activation	Disease/Application	Refs.
In Vitro	NIR-triggered LrPC or PEGylated LrPC with PLGA NPs loaded with mTHPC	NIR light	PDT for cancer therapy	[54]
	Amphiphilic polymer NPs with UV/light and temperature-responsive properties containing SIP and PDMAEMA	UV light + temperature	Drug delivery with dual stimuli response	[55]
	NIR-triggered PEGylated LrPC and PLGA NPs loaded with mTHPC	NIR light	PDT to treat gastrointestinal cancer treatment	[56]
	Dendrimer-based star-shaped copolymer with light- and pH-responsive properties for DOX delivery	UV + PH	Cancer therapy using hydrophobic drug carriers	[57]
	Coumarin-based copolymers on HMS@C18 modified with folic acid	NIR light	Cancer therapy and imaging applications	[58]
	Two-photon responsive mesoporous organosilica nanocarriers (M2PS) with disulfide nano gates	Two-photon (NIR light/UV light-visible light)	Cancer therapy	[59]
	NIR light-triggered NPs encapsulating DOX and CP, with cRGD targeting	NIR light	(Cancer treatment) synergistic approach of PTT and chemotherapy	[60]
	UCNPs coated with mesoporous silica and loaded with DOX, gated by Ruthenium complexes	NIR light	Cancer therapy	[61]
	Mesoporous silica-coated UCNPs with Py and β-CD nanovalves	NIR light (converted to UV light)	Cancer therapy (HeLa cells)	[62]
	low-power, NIR or UV light-triggered polymers	NIR or UV	Drug delivery in deep tissue applications	[63]
In Vivo	Yolk-shell nanocage system with a mesoporous silica shell and UCNP core, loaded with chlorambucil	NIR light	Cancer therapy	[64]
	NIR-triggered nanocomposites combining UCNPs and DOX in a photo-responsive copolymer	NIR light	Cancer therapy (antitumor efficacy with minimal side effects)	[65]
	NIR and pH-responsive NPs with PEGylation/dePEGylation strategy, UCNPs, and iRGD peptide	NIR light + PH	Cancer (improved tumor penetration)	[66]
	NIR-triggered azobenzene polymers and U/DCNP nanocapsules	NIR light	Cancer therapy (controlled drug release)	[67]
	NIR- triggered charge-convertible UCNPs with Pt(IV) and PEG-PAH-DMMA coating	NIR light	Cancer therapy (enhanced chemotherapy with cisplatin)	[68]
	NIR-triggered microneedle patch loaded with W379, IR780, and coated with 1-TD	NIR light	Wound biofilm treatment	[69]

below outlines the type of application (in vivo or in vitro), the materials utilized, and the targeted applications and diseases.

Table 8 shows the recent advancement and progress of both in vitro and in vivo studies, which are resulting in promising preclinical results. However, to apply these findings in clinical settings, challenges such as allowing light to reach deeper tissues and ensuring that materials are safe for long-term use still need to be addressed.

9.3. Future Directions and Research Recommendations

Future studies should focus on improving light penetration into deeper tissues, as this remains a primary limitation of light-triggered systems. This challenge could be addressed by developing advanced two-photon absorption systems or utilizing upconversion nanoparticles. Additionally, research should evaluate the long-term biocompatibility and biodegradability of nanocarriers, which are critical for ensuring their safety in clinical applications. Finally, exploring the integration of light-triggered therapies with other emerging fields, such as immunotherapy, could unlock new treatment possibilities.

10. Conclusions

This paper reviews studies on light-triggered drug delivery systems for treating various diseases, including cancer. Focusing on photodynamic therapy (PDT), photothermal therapy (PTT), and their in vivo and in vitro applications, these studies aim to overcome the limitations of traditional drug delivery methods, such as non-specific biodistribution and low selectivity. Many of the reviewed studies emphasize the effectiveness of synergistic combinations of PDT and PTT with other approaches to enhance treatment outcomes and address the limitations of using these therapies individually. These enhancements include the potential for minimally invasive drug delivery and reduced toxicity to healthy tissues. However, challenges such as limited light penetration for treating deeper tissues and material biocompatibility require further investigation. Future research should focus on optimizing these systems for clinical applications, improving light penetration techniques, and exploring new light-triggered materials to fully realize their therapeutic potential.