Hydrogels are three-dimensional crosslinked polymeric networks that can absorb large amounts of water or biological fluids. Their structures are formed through chemical or physical crosslinking of different polymer chains, between which either covalent bonds or physical interactions exist to maintain their structural stability (Ebara et al., 2014). Hydrogels are usually characterized with pH-neutral, colorless, odorless, non-toxic, high absorption ability, and excellent stability and constancy in storage with controllable biodegradability (Ullah et al., 2015). Given their technical features, hydrogels have been utilized in designing drug delivery systems for years. Hydrogels can protect the drug from surrounding environments, and their tunable properties plus the ability to retain large fraction of solvents make them ideal carriers for drug delivery systems. By changing hydrogel properties, drug release rate can be accurately controlled. Additionally, hydrogels usually have low affinity with drugs, thus achieve a high fraction of drug release.

Hydrogels can be classified into two groups according to their responses to external stimuli: one is conventional hydrogels, which have no particular sensation to changes of their environment, and the other is stimuli-responsive hydrogels, also known as smart hydrogels that are capable of responding to physical, chemical or biochemical stimuli (Ji et al.eng, 2020). In response to external stimuli, these hydrogels undergo a series of changes in their growth actions, network structure, mechanical strength and permeability (Zhang et al., 2021; Gil and Hudson, 2004/12). Stimuli-responsive hydrogels contain specific components as “on-off” sensors able to detect stimulation signals and subsequently control their changes. For example, ultrasound amplitude and time duration are associated FITC-BSA release rate in chitosan hydrogels with reversible Diels-Alder linkers (Arrizabalaga et al.eng, 2022); and thermosensitive mPEG-PA-PLL hydrogel was used for controlled oral delivery of calcitonin (Cheng et al., 2022). Combining two or more stimuli responsive mechanisms in one hydrogel system, multi-responsive hydrogels can be formed to respond to more than two external stimuli. PF127/TMC/PEG-HA can react to both pH and temperature, and is an example of a dual responsive hydrogel used for in textile-based transdermal therapy (Chatterjee et al., 2019).

Light responsive hydrogels are able to respond to light irradiation and subsequently give rise to structural and conformational changes (Jiang and Wen, 2015; Bustamante-Torres et al., 2021). Light is an easy acquired, effective and non-invasive external stimulus that can be highly focused and regulated by manipulating its parameters, including intensity, wavelength, exposure time and beam diameter. Consequently, light offers accurate and spatiotemporal control of drug delivery, and thus received great attention in the past decade (Li et al., 2018a; Rizzo et al., 2021). Light responsive hydrogels are obtained by incorporating photosensitive moieties into the polymer structure. Based on the photosensitizer (PS) used, the response can be reversible or irreversible (Bustamante-Torres et al., 2021). Light can cause cleavage, isomerization, or dimerization of photosensitive groups in hydrogels, and leads to partial or complete decrosslinking, degradation, swelling and/or shrinkage of the hydrogel structure.

The light-controlled drug delivery systems can be classified into three broad categories: photoisomerization-based, photochemical-based, and photothermal-based drug release platforms. Photoisomerization typically involves conformational changes of the hydrogels from trans to cis under light irradiation. During this process, hydrogels open pore sizes and allow drugs to diffuse out of their matrixes (Figure 1A). It does not break chemical bonds of hydrogels, and the process is usually reversible and repeatable (Tomatsu et al., 2011). Photochemical reactions can lead to network structure and configuration changes of the hydrogel, and subsequently induce drug release (Iwaso et al., 2016). Among all photochemical reactions, photocleavage is the one of most commonly used ones for controlled drug delivery. This method is realized by incorporating photocleavable linkers into the hydrogel structure to create nanoparticles that can be cut off by light (Figure 1B) (Miranda and Lovell, 2016; Liese and Hampp, 2011/04). In this case, drugs are tethered to the hydrogel network at designed or selected sites covalently through photocleavable linkers, and can maintain their efficacy and avoid unwanted release to a large extent (Shadish and DeForest, 2020; Wang et al., 2020). The photothermal reaction is utilizing materials able to convert light energy into the heat energy, which in turn induces a disruption of a thermally sensitive drug carrier (Figure 1C) (Qiu et al., 2018; Bordbar-Khiabani and Gasik, 2022). The reaction requires two components - a photosensitizer to convert light into heat, and a material sensitive to temperature changes for drug release.

The commonly used light sources include ultraviolet (UV), visible light and near-infrared (NIR). UV once was the most popular light sources because of the availability of a wide range of UV photosensitizers. But it is mainly for in vitro experiments due to its cytotoxicity and low tissue penetration. On the side, NIR is safer for in vivo studies and able to trigger drug release within deep tissues. Thus, NIR is very attractable for clinical applications. Due to recent advance of material science, many new photosensitizers responsive to NIR were developed. Additionally, the use of two-photon excitation (Figure 1D) and up-conversion nanoparticles (UCNPs) (Figure 1E) also greatly expanded situations that NIR can be used (Pokharel and Park, 2022; Yuan et al., 2015; Yan et al., 2012/10). Based on above mechanisms, a variety of drug delivery applications were presented in Table 1 (Tao et al., 2019; Liang et al.eng, 2020; Pourjavadi et al., 2020; Wei et al., 2020; Yu et al., 2020).

Photoisomerization takes advantage of the conformational changes of certain molecules when stimulated by light irradiation (Pan et al., 2021/10). Azobenzene is the most used molecules in this category. Modifying hydrogels with azobenzene and cyclodextrin (CD) can create light responsive crosslinking between the two components. When in the trans isomer form, azobenzene can have “host-guest” interaction with CD, forming strong crosslinks. Under UV light irradiation, the azobenzene changes to cis isomer form which leads to breaking of crosslinks and drug release.

Light responsive azobenzene-CD guest-host chemistry has been widely used for controlled release of drugs from hydrogels under light exposure (Rosales et al., 2018). In one study, the authors developed a light responsive hydrogel by permeating diazobenzene-modified poly(ethylene glycol) (PEG) into βCD grafted alginate. Exposure of UV light leads to controlled cargo release from the hydrogel which was used in wound healing and other applications (Chiang and Chu, 2015). In another study, a model drug was released from a light responsive hydrogel made from azobenzene and PEG. The system showed reversible photoisomerization between its cis and trans isomers under UV-light irradiation allowing model drug release from the hydrogel network. The authors observed clear volume changes during the photoisomerization process and characterized the peak effects at 330 nm and 435 nm respectively. Thus, the drug release can be controlled by the wavelength and intensity of light irradiation (Rastogi et al.eng, 2018). Additionally, Nehls et al. showed similar results with more accurately controlled release rate of an entrapped model drug based on azobenzene-CD chemistry in PEG hydrogels (Nehls et al., 2016). Furthermore, PAA-based hydrogel modified with methoxy-substituted azobenzene and βCD supramolecular complexes showed a gel to sol transition in response to red light irradiation, and subsequently resulted in a dose dependent manner of loaded BSA release. With higher wavelength than UV, red light can be used for deep tissue drug delivery with less energy-induced damage (Wang et al., 2015). Chen et al. designed a DOX-loaded delivery system targeted tumor tissues using muli-responsive formation and degradation of the hydrogel (Figure 1F) (Chen et al.eng, 2016).

Spiropyran is another well-known photosensitizer that can be incorporated into hydrogel networks. It was used to deliver a variety of drugs such as doxorubicin and paclitaxel based on photoisomerization of hydrophobic spiropyran to hydrophilic merocyanine after UV irradiation. During this process, the swelling of hydrogels cause water soluble drugs to diffuse out of the hydrogel networks (Li et al., 2020/05). Tong et al. reported a nanoparticulate drug delivery system comprising spiropyran and PEGylated lipid that allows repetitive drug delivery at given time and location. The light-sensitive switch enables particles to fluoresce and release drugs inside cells when illuminated with UV light providing a spatiotemporal control of drug delivery with and enhanced tissue penetration (Tong et al., 2012). Spiropyrans within hydrogels have also been used as on and off switch triggers for controlled drug release in a number of other studies due to its reversible properties (Ghani et al., 2021/01; Xiao et al.eng, 2016).

Photochemical reactions include photooxidation, photocleavage and photopolymerization. For photocleavage induced drug release, o-nitrobenzyl is the most popular photocleavable linkers. It can be incorporated into many hydrogels to give them light responsive properties. The cleavage of o-nitrobenzyls happens at C-O bond in its ester group after exposure to UV light or high energy visual light. In one study, o-nitrobenzyl moieties were added into gelatin methacryloyl(-acetyl) hydrogels with a biotin-functionalized photocleavable macromer, and then controlled release under UV-irradiation is studied. The authors found that liquid chromatography coupled to mass spectrometry analysis of aqueous linker solutions allows the identification of the main cleavage products and the cleavage kinetics (Claaßen et al., 2018). O-nitrobenzyls were also used to cause a macro physical change in the overall structure for drug delivery (Linsley et al., 2017). In o-nitrobenzyl linked PEG and PAM hydrogels, cleavage of o-nitrobenzyls with UV resulted volume shrinking of their polymeric structure, and caused controlled release of drugs entrapped within its matrix (Yan et al., 2012/10). In a similar study for PEG and dextran hydrogel with o-nitrobenzyl linkers, 60 min exposure to UV leads to fifty percent of model drug release due to hydrogel structure dissociation (Peng et al., 2011). In another study, authors showed a novel strategy enabling the use of upconversion luminescence converting NIR light into UV light, which are received by o-nitrobenzyl groups in PEG hydrogels. Subsequently, the photocleavage reaction leads to tethered drugs (Yan et al., 2011/12).

A ruthenium-based photocleavable linker was developed to form hydrogel with entrapped model drugs, which cannot be released until exposure to light. By varying the coordinated ligands, Ru-cross-linkers have 1-photon absorption maxima that are tunable across the visible spectrum and into the near-infrared, which enables photoactivation at multiple, different wavelengths (Rapp and Dmochowski, 2019). In a more recent study, Yerneni et al. tethered exosomes to poly(ethylene oxide)-based hydrogels using atom transfer radical polymerization. The method allowed controlled release over a period of 1 month and the release profile can be programmed through crosslinking density and light stimuli conditions (Yerneni et al.eng, 2022). Yang et al. developed a photocleavable prodrug loaded injectable glycol chitosan (GC) hydrogel for NIR-triggered repetitive drug release. The hydrogel shows good stability, minimum leakage and efficient light responsibility both in vitro and in vivo (Yang et al., 2022).

When photocleavable linkers attach model drugs to polymer matrix covalently, it may cause great reduction to drug activities as well as unspecified tethers. To overcome these disadvantages, some researchers used recombinant protein techniques to modify proteins with a handle in order to attach a protein of interest to the hydrogel matrix. In one study, a PEG-based hydrogel was developed via a click reaction without impact on entrapped enzyme activity under 60°C thermal stress for weeks. The study showed a general method to preserve drug activities at certain conditions and enable controlled drug release when needed (Sridhar et al., 2018/03). In another study, the authors developed a technique to use light-sensing proteins as light-activated reversible binding sites within synthetic poly(ethylene glycol) (PEG) hydrogels. It has reversible changes between “light” and “dark” conformations in response to different lights to control a recombinant protein release from PEG hydrogels spatiotemporally (Hammer et al., 2020/07). In a recent study, both nitrobenzyl and coumarin were used for photolabile crosslinks, and subsequently, on-demand and tunable dual wavelength release of antibody was achieved (Figure 1G) (LeValley et al.eng, 2020).

Photothermal therapy-based drug delivery system includes a photothermal agent, which is able to generate heat through light irradiation. The heat energy is then used to trigger reversible structure changes of thermal-responsive hydrogels, subsequently cause drug release from the system (Pan et al., 2021/10). Some commonly used photothermal agents include both inorganic nanoparticles and organic compounds, such as rare metal nanostructures and black phosphorus (BP) nanoparticles, which have little phototoxicity. These photothermal agents have minimized damage to cells and good penetration for high efficiency, and thus can provide safe thermal effects for controlled drug release (Zhang et al., 2015; Zhu et al., 2015; Wang et al., 2016; Yang et al., 2018). Commonly used thermal-responsive hydrogels include poly(N-isopropylacrylamide) (PNIPAAm), thermosensitive PEG analogs and thermosensitive elastin peptides (ELPs) (Ward and Georgiou, 2011). Because high temperature can lead to cell necrosis, the parameters of applied light irradiation should be carefully selected to avoid thermal damage to surrounding areas of targeted cells or tissues (Yang et al.eng, 2017). For this reason, NIR light is widely used to initiate photothermal effects because of its low energy and deep penetration properties. The drug release parameters can be accurately controlled by light duration and intensity, concentration of photothermal agents, and hydrogel composition (Merino et al., 2015).

BP nanoparticles are one of the most popular photothermal agents. Qiu et al. developed a low–melting-point agarose drug delivery nanostructure containing BP. After injected into cancer tissue, the hydrogel experiences a phase transition to gel states at body temperature. Under NIR irradiation, the hydrogel entered in a melting state which caused drug release from its matrix. Additionally, the release rate is able to be accurately controlled (Qiu et al., 2018). The system demonstrated a high therapeutic efficacy for cancers, and it is harmless and degradable in vivo. In another study, an injectable, NIR-II light-modulated and thermosensitive hydrogel is synthesized through supramolecular self-assembly of a conjugated polymer and alpha-cyclodextrin. This hydrogel intrinsically features NIR responsive characteristics and thermo-responsive properties (Figure 1H) (Ruan et al., 2019).

Rare metals are also widely used as photothermal agents. In one study, platinum nanoparticles were integrated into a NIR light-responsive hydrogel consisting of αCD and PEG-modified dendrimer. Under NIR irradiation, this hydrogel underwent a disruption to release the encapsulated drugs in a controlled manner via the irradiation time (Wang et al., 2016). Platinum nanoparticle has a very good photothermal conversion efficiency and biocompatibility; thus, it is frequently used with hydrogels for drug delivery. In another similar study, aldehyde-modified dextran hydrogel containing dendrimer-encapsulated platinum nanoparticles were developed via imine bond formation. The hydrogel exhibited excellent biocompatibility, photothermal effect and biodegradable properties. It can stay in tumors for days to allow repeated drug release, resulting in tumor regression (Li et al., 2018b).

For a study using organic compounds as the photothermal agent, one type of PNIPAM hydrogel has been synthesized with protoporphyrin IX or pheophorbide as photothermal agents, which are covalently conjugated to the polymer chains. The hydrogels showed great biocompatibility with more than 90% cell viability even at very high photosensitizer concentration suggesting the hydrogels can be applied for photothermal therapy (Belali et al.eng, 2018). In another study, the authors designed a novel type of dynamic-covalent hydrogel (GelPV-DOX-DBNP) for combined chemical and photothermal therapy of cancers. Anticancer drug DOX and photosensitizer perylene diimide zwitterionic polymer (PDS) as well as reductant ascorbic acid (Vc) were encapsulated. Under 600 nm light irradiation, PDS and VC can turn oxygen to hydrogen and cause degradation of hydrogel, subsequently lead to DOX and DBNP release from hydrogel. DBNPs are able to generate heat under NIR irradiation, making the system a useful drug delivery platform (Sun et al.eng, 2020). Cao et al. developed a chemo-photodynamic therapy system using ROS sensitive structure and successfully used for cancer treatment (Figure 1I) (Cao et al., 2018).

Multi-stimuli responsive hydrogels have been used in a variety of physiological or pathological conditions. Besides responding to light, hydrogels can also be designed to respond to pH, magnetic field and reductant etc (Sharifzadeh and Hosseinkhani, 2017; Pham et al., 2020). In one study, hydrogels that can respond to both pH and NIR is designed to release adamantane-modified doxorubicin (DOX) prodrug using N-isopropylacrylamide (NIPAm) and βCD-based hydrogel. The pH-responsive release of DOX from the nanocomposite hydrogel was observed owing to the cleavage of acid-labile hydrazone bond between DOX and the adamantyl group in acidic environment. NIR irradiation led to accelerated release of DOX from hydrogels because of photothermal effects. The hydrogel can respond to both pH and NIR light and speed up drug release rate in a controlled manner (Xu et al.eng, 2017). In another study combining light and magnetic field, the authors designed a temperature-responsive PNIPAm hydrogel microfibers with controlled shapes and sizes. Then they fabricated light-responsive materials by incorporating photothermal magnetic nanoparticles within the PNIPAm microfibers. The magnetic nanoparticles were incorporated into the PNIPAm microfibers and created heat when subjected to visible light exposure. Volume changes of the PNIPAm hydrogel can be induced by both light irradiation and temperature, suggesting its potential use for drug delivery (Lim et al., 2015). Shao et al. developed a PEG based nanocarrier with light and redox dual responsive properties for cancer therapy. The system possesses good drug loading capacity and stability, and showed preferred tumor accumulation and the prolonged tumor residency by in vivo and ex vivo experiments (Shao et al., 2014). In another study, photo, pH and redox multi-responsive nanogels were developed for drug delivery and fluorescence cell imaging (Chen et al., 2017) (Figures 1J, K). Multi-stimuli responsive hydrogels are multi-functional, and suitable for multi-step drug delivery systems especially for complicated in vivo studies.

Light is a powerful trigger for controlled drug delivery systems. Intensity, spatial and temporal control of light allows excellent manipulation of therapeutic agents in comparison with other physical, chemical, and biological stimuli (Chen et al., 2020). So far, much progress has been made in developing of innovative light responsive hydrogel drug delivery systems with both breadth and depth. But translating these studies into clinical applications still poses a significant challenge. Major issues need to be addressed includes: 1) most tumors are deep within the body, and it is difficult to deliver drugs to these locations. 2) the in vivo biological conditions of human are complex, therapeutic effects of drugs are low comparing in vitro or animal studies. 3) biomaterials of the drug delivery system, including hydrogel, photosensitizer, drug carrier and other components, may accumulate within human body after long-term administration. 4) most light induced drug delivery systems are irreversible, which made drug release inconsistent during the process. 5) non-specific photoreactions in normal tissues need to be considered. 6) photosensitizers are still active in dark conditions, and thus stability of loaded drugs cannot be maintained especially for long-term use.

Considering above issues, potential future developments may include: 1) designing photosensitizers responsive to low energy light source with fast response, high efficacy and deep tissue penetration (Li et al., 2019). Low energy lights, such as NIR, also cause less non-specific phototoxicity in normal tissues. 2) characterizing in vivo biological conditions, such as pH, temperature, redox and enzymatic reactions. These stimuli should be used together with light for drug release. 3) developing highly biocompatible materials for drug delivery systems. Natural biomaterials that mimic human tissues may be promising. 4) combing photoisomerization with other reactions to design reversible systems. Light-responsive proteins may have wider applications for this purpose (Tao et al., 2020). 5) besides using low energy light, monitoring real time drug distribution within tissue is another way minimize non-specific photoreactions. 6) developing stable photosensitizers for long-term stable drug release. Additionally, combining two or more independent photo-induced reactions into one drug delivery system is appealing for clinical use (LeValley et al.eng, 2020).