Strategies to enhance the effects of nanotechnology-mediated photodynamic therapy

ABSTRACT

Photodynamic therapy (PDT) is a noninvasive therapeutic approach, particularly effective in tumor treatment. PDT utilizes photosensitizers (PSs) to absorb light at specific wavelengths, converting photon energy into chemical energy and subsequently generating cytotoxic reactive oxygen species (ROS). These ROS trigger cell death through apoptosis, necrosis and autophagy-related pathways. Compared with conventional therapies, PDT exhibits significant advantages, including high selectivity, repeatability, enhanced safety, minimal side effects, low drug resistance, and compatibility with radiotherapy or chemotherapy. However, due to the limited tissue penetration depth of light, PDT demonstrates suboptimal efficacy in treating deep tumors. Additionally, limitations such as poor targeting of photosensitizers and unfavorable factors in the tumor microenvironment greatly restrict PDT’s therapeutic efficacy and clinical applicability. To enhance PDT efficacy, various strategies have been explored, among which nanotechnology has emerged as a key research focus. This review summarizes multiple approaches to augmenting nanotechnology-mediated PDT, with emphasis on achieving targeted delivery of photosensitizers (tissue, cell, and organelle-level), improving the performance of photosensitizers and modulating the tumor microenvironment. These insights provide theoretical guidance and practical references for developing novel and efficient PDT nanoplatforms. We conducted the literature search in PubMed, Elsevier ScienceDirect, Web of Science, Wiley and Scopus (from 2004 to 2025).

1. Introduction

Photodynamic therapy (PDT) is a noninvasive therapy, especially for tumor treatment. During PDT, photosensitizer could convert photon energy into chemical energy under the irradiation of a light source at specific wavelength and generate cytotoxic reactive oxygen species (ROS) [1], including singlet oxygen (¹O₂) and other cytotoxic oxygen species, such as superoxide anion radical (O₂-) and hydroxyl radical (·OH) [2]. ROS would trigger cell death through apoptosis, necrosis, and autophagy-related pathways [3]. PDT offers numerous advantages, including high selectivity, reproducibility, high safety, low toxicity [4], low drug resistance [5,6], and combinable with radiotherapy or chemotherapy [7]. Meanwhile, as a localized therapy, PDT not only directly eliminates tumor cells [8], but also triggers inflammatory response and activates the body’s anti-tumor immune system [9].

Despite its potential, PDT still faces several challenges in clinical applications. First of all, the physicochemical properties of most photosensitizers present fundamental challenges – their hydrophobic nature leads to aggregation and poor biocompatibility in vivo, resulting in suboptimal bioavailability [10]. Traditional photosensitizers also exhibit inadequate optical characteristics, including restricted spectral absorption ranges and insufficient quantum yields, which compromise their therapeutic efficacy [11]. Second, the lack of targeted delivery systems results in nonspecific distribution of photosensitizers, potentially causing unwanted phototoxic effects in normal tissues [12]. Furthermore, the extremely short lifespan and limited diffusion distance of ROS require that photosensitizers must be delivered precisely to the target location for optimal therapeutic effect. Lastly, complex tumor microenvironment (TME), characterized by hypoxia, antioxidant system, and immunosuppressive conditions would also impede the therapeutic efficacy of PDT [13].

Fortunately, recent advances in nanotechnology have provided many effective strategies for enhancing the efficacy of PDT. Primarily, nanotechnology offers sophisticated drug delivery platforms, which could effectively improve the bioavailability and stability of photosensitizers. These platforms can be engineered with targeting capabilities, enabling precise localization of photosensitizers to tumor tissues, cells, or even specific subcellular organelles. These strategies not only minimize toxic side effects caused by nonspecific distribution, but also enhance the tumor-killing ability of ROS. Secondly, in terms of photosensitizer performance modification, a variety of innovative nanomaterials have been developed as photosensitizers, including metal-organic nanoframes, aggregation-induced luminescent materials, and upconversion nanoparticles. These nanoscale photosensitizers often demonstrate superior photostability, enhanced tissue penetration, and higher quantum yield, thereby improving both the generation and distribution of ROS. In particular, the implementation of autoluminescent systems, such as chemiluminescence, as alternatives to external light sources has effectively addressed the limitation of insufficient light penetration in deep tissues. Such strageties provide novel solutions to clinical challenges, particularly in treating deep tumors. Lastly, diverses strageties based nanoplatform have been designed to enhance PDT efficacy and improve the tumor microenvironment, including strategies to ameliorate hypoxia, inhibit the antioxidant system, remodel the extracellular matrix, and diminish immunosuppression.

In summary, we primarily conducted a literature search based on the process of PDT, including the targeted delivery of photosensitizers, methods of ROS generation, effects of ROS (yield/tissue penetration depth), and the impact of tumor microenvironment on PDT efficacy, in PubMed, Elsevier ScienceDirect, Web of Science, Wiley and Scopus (from 2004 to 2025). The paper systematically reviews the research progress of nanotechnology-enhanced PDT, with particular emphasis on three critical aspects: targeted delivery systems, innovative photosensitizer development, and tumor microenvironment regulation. We focused on the different nanoplatform applications across these strategies, aiming to serve as a valuable resource for future innovations in nanoplatform design (Figure 1).

Figure 1.

Strategies to enhance the effects of nanotechnology-mediated photodynamic therapy. Created in BioRender. Shi, M. (2025) https://BioRender.com/3trx3o5.

2. Targeted delivery of photosensitizers

Targeted strategies can enhance the accumulation of photosensitizers in tumor tissues, thereby increasing tumor cell destruction and improving PDT efficacy while reducing potential toxicity caused by nonspecific distribution of photosensitizers.

2.1. Subcellular organelle targeting

The advantages of subcellular organelle targeting are increased specificity and precision, and reduced dosage requirements. This strategy is particularly advantageous in PDT, where the controlled generation of ROS can be directed to specific subcellular compartments, resulting in more efficient and targeted tumor cell elimination [14]. In addition, ROS have a very short lifetime (0.03–0.18 ms) and a limited diffusion distance (0.01–0.02 μm) within tumor cells, resulting in a highly localized range of activity [15,16]. Therefore, photosensitizers targeting vulnerable organelles can greatly improve the efficacy of PDT compared to those that remain in the extracellular matrix.

2.1.1. Endoplasmic reticulum targeting

Endoplasmic reticulum (ER) has important biological functions as an indispensable organelle in cells. When a large amount of ROS is generated in the ER, the accumulation of misfolded proteins will interfere with endoplasmic reticulum homeostasis, triggering endoplasmic reticulum stress, which leads to apoptosis [17]. Therefore, ER can be an effective target for PDT.

To enhance ER targeting, nanoparticles can be modified using ligands [18]. Zhang et al. designed a polymer containing aggregation-induced luminescence (AIE) molecular units in the backbone, and self-assembled the polymer with an ER-targeting ligand (N-toluene-sulfonylethylenediamine) and a bone-targeting ligand (alendronate) to form targeted nanoparticles (NPER/BO-PDT) for the treatment of osteosarcoma [19].

The surface of nanoparticles can also be modified with specific targeting peptides to promote ER-targeted delivery of photosensitizers [20,21]. Zheng et al. prepared ER-PPB by combining the ER-targeting peptide, FFKDEL, a hydrophilic PEG junction, and the photosensitizer protoporphyrin IX into an amphiphilic chimeric peptide (ER-PP), and then assembled it with a PD-1/PD-L1 blocking agent. ER-PPB was passively targeted to tumor tissues, it selectively accumulates in the ER and generates large amounts of ROS to exert local PDT effects (Figure 2) [22]. Similarly, Liang et al. used the ER-targeting peptide KDEL to deliver photosensitizers [23].

Figure 2.

Chemical structure of chimeric peptide-engineered immunostimulant and the proposed mechanism for endoplasmic reticulum (ER) targeted photodynamic immunotherapy. Reprinted with permission from [22]. Copyright 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

2.1.2. Mitochondria targeting

Mitochondria, as the main site of cellular aerobic respiration, maintain redox homeostasis, and increase ROS generation and trigger apoptotic pathways when disturbed or damaged [24]. Therefore, mitochondria-targeting strategies have been applied to improve the efficacy of PDT [25].

Mitochondria of tumor cells are hyperpolarized (−220 mV) compared to mitochondria of normal cells (−157 mV), so positively charged drugs can target mitochondria [26]. Several positively charged molecules have been designed as nanophotosensitizers [27,28]. Fang et al. designed nanoparticles of pyridocyanine, a bovine serum albumin (BSA)-bound photosensitizer (PSs@BSAs), where the positive charge of pyridocyanine induces a precise accumulation of pyridocyanine in the mitochondria, which effectively inhibits the mitochondrial activity, and through the PDT effect further disrupting tumor angiogenesis and triggering metabolic and oxidative stress imbalance [29]. In addition, the use of positively charged nanocarriers also allows for the targeted delivery of photosensitizers to mitochondria [30]. Peng et al. [31] prepared positively charged nanomicelles using an amphiphilic copolymer containing TPP, a cation, for the loading and delivery of the photosensitizer, dihydroporphyrin e6 (Ce6), to mitochondria. The results showed that the nanodrug delivery system could efficiently kill tumor cells by generating ROS in mitochondria and enhancing the immune response [31].

Mitochondrial targeting strategies based on transporter proteins have been applied to PDT. Transporter proteins (TPSOs) are widely expressed in many types of tumor cells, including breast, colorectal, and pancreatic cancers, and are predominantly distributed in the outer mitochondrial membrane [32,33]. Mingfeng Bai’s team has developed a series of therapeutic TSPO-targeted photosensitizers (TSPO-PSs), which exhibit excellent target-specific PDT effects under near-infrared light irradiation, effectively inducing immunogenic tumor cell death (colorectal cancer cell lines and pancreatic cancer cell lines) [34,35].

Targeting peptides represent another effective strategy. Jiao et al. developed nanoparticles by coupling a mitochondria-targeting peptide sequence (Phe-Arg-Phe-Lys) with clonidine and self-assembling it with the photosensitizer PpIX. These nanoparticles demonstrated effective mitochondrial targeting for PDT [36].

2.1.3. Cell membrane targeting

Cell membrane-targeted PDT disrupts membrane integrity, increases membrane permeability, induces lipid peroxidation, and ultimately leads to rupture of the cell membrane and release of cellular contents, resulting in cell death [37].

A variety of cell membrane-targeted chimeric peptides coupled to photosensitizers have been developed for the construction of cell membrane-targeted PDT nanosystems, including C₁₆-PRP-DMA (C₁₆-K(PpIX)RRK(DMA)K(DMA)-PEG-COOH) [38], ChiP (C₁₆-K(PpIX)-PKKKRKV) [39], PCPK (PpIX-C⁶-PEG₈-KKKKKKKSKTKC-OMe) [40], Ac-K(PpIX)-R_n)/Ac-K(PpIX)-E_n [41], CMP-PpIX (C₁₆-K(PpIX)GRRRR-AEEA-K(FAM)SDEVDSK-(Dabcyl)PEG₍₈₎PEG₈) [42], RKC (C-RKRKRKRKRK-C16) [43], CPP (C₁₆-Cypate-RRKK-PEG₈-COOH) [44], PMTP (C₁₆-K(PpIX)-RRGGCNGRC) [45].

Strategies to enrich cell surfaces with photosensitizers via bioorthogonal reactions have also been proposed. Xiao et al. designed a novel nanoparticle based on aggregation-induced emission (AIE) photosensitizers (BODTPE), a system capable of targeting cell membranes via bioorthogonal copper-free click chemistry to enhance the PDT/PTT/NIR-II FLI effect and activate the cGAS-STING pathway [46]. Dan Ding’s team engineered an alkaline phosphatase (ALP) and cholecystokinin-2 receptor (CCK2R) dual-targeting peptide called DBCO-pYCCK6, which selectively and rapidly self-assembles on tumor cell membranes, followed by enrichment of type I PS (SAIE-N₃) on cell membranes via bioorthogonal reactions. In the presence of light, membrane-anchored SAIE-N₃efficiently generates ROS and induces gasdermin E (GSDME)-mediated cellular focal death [47].

2.2. Tumor cell targeting

2.2.1. Passive targeting

The abundance of blood vessels in solid tumor tissues, wide interstitial spaces in the vessel wall, poor structural integrity, and lack of lymphatic return make macromolecules and lipid particles selectively highly permeable and retentive, i.e., they tend to aggregate more in tumor tissues. Tumor passive targeting of photosensitizers can be achieved using nanocarriers through enhance permeability and retention effect [48]. Zhang et al. prepared an ultra-small-sized self-assembled nano-photosensitizer with a hydrophilic TEG coating and a positively charged surface that endowed the nanoassemblies with prolonged blood circulation and positively charged-mediated tumor-targeting capabilities, respectively, prompting preferential accumulation in tumors with a tumor/normal cell distribution ratio as high as 11.5 [49].

2.2.2. Active targeting

Since antigens or receptors specifically expressed on the surface of tumor cells exist, modification of corresponding antibodies or ligands on the surface of nanocarriers, taking advantage of specific binding characteristics of antigen-antibody and receptor-ligand, can achieve active tumor targeting of photosensitizers [21,50,51]. Montaseri et al. found that an active targeting strategy significantly enhanced the cellular uptake of nanoparticles compared to passive targeting [52]. Epidermal growth factor receptor (EGFR) is a glycosylated transmembrane receptor tyrosine kinase that is closely associated with tumorigenesis and cancer proliferation. Due to its overexpression in tumor cells, EGFR is a crucial target in cancer therapy [53]. Chen et al. constructed photodynamic nanoantibody couplings MNB-Pyra Nbs by combining EGFR-specific nanoantibodies with the type I photosensitizer MNB-Pyra, which demonstrated efficient tumor targeting ability and PDT efficiency [54]. Chen et al. designed photosensitizer PS-02 self-assembled nanoparticles with surface modification of saccharin derivative (6-NS), a targeting ligand of tumor biomarker carbonic anhydrase IX (CAIX), for tumor cell-targeted recognition and enrichment [55]. Wang et al. developed a multifunctional NIR-II-emitting small molecule photosensitizer nanoparticle, which was coated with mouse pancreatic tumor cell membranes to confer biomimetic properties, thereby enhancing tumor targeting and effective treatment of pancreatic cancer (Figure 3) [56]. In addition, active targeting of photosensitizers to tumor cells can also be achieved by modifying folic acid [57], nucleic acid aptamers [58], and specific proteins on the surface of nanocarriers [59].

Figure 3.

Schematic showing a NIR-II-emissive organic nanomedicine with biomimetic engineering for bioimaging targeting and multiple phototherapies of pancreatic tumors. Reprinted with permission from [56]. Copyright 2024 Wiley‐VCH GmbH.

2.3. Tissue targeting strategies

Stimulus-responsive nanocarrier systems, which respond to tumor microenvironmental factors, can precisely control drug release on demand, improving therapeutic efficacy while reducing systemic toxicity [60].

2.3.1. PH responsiveness

The tumor microenvironment exhibits characteristically lower pH values compared to normal tissues [61], enabling acid-sensitive nanocarriers to trigger pH-responsive release of photosensitizers while enhancing cellular internalization [62,63]. Yang et al. developed a near-infrared aggregation-induced emission (AIE) luminogen, DBP-SPy, by incorporating pH-sensitive sulfonamide moieties with AIE photosensitizers. In aqueous media at physiological pH, DBP-SPy self-assembles into negatively charged nanoaggregates that undergo charge reversal to positive surface potential in the acidic tumor microenvironment. This charge conversion facilitates enhanced cellular uptake through electrostatic interactions with the negatively charged cell membranes, resulting in superior PDT efficacy [64]. Dong Xiaochen’s team engineered tumor-acidity-activated calcium phosphate nanocarriers (TACC NPs) co-encapsulating thrombin (Thr), the hypoxia-activated prodrug AQ4N, and the photosensitizer chlorin e6 (Ce6). These nanocarriers demonstrate excellent stability under physiological conditions while undergoing pH-triggered dissolution in the acidic tumor microenvironment to release their therapeutic payload [65]. Furthermore, acidic pH can directly activate photosensitizers to initiate PDT [66]. Chai et al. developed three pH-responsive NIR-II photosensitizers (RBT-pHs) through helical lactam ring closure, with RBT-pH-1 being subsequently encapsulated in DSPE-mPEG5k to form nanoparticles (RBT-pH-1 NPs). Notably, RBT-pH-1 demonstrates tumor microenvironment-selective activation of its photosensitizing properties under acidic conditions for targeted PDT applications [67].

2.3.2. GSH responsiveness

The hypoxic tumor microenvironment (TME) induces elevated intracellular glutathione (GSH) concentrations in malignant cells compared to normal tissues [68]. GSH mediates the structural disintegration of redox-responsive nanocarriers through disulfide bond cleavage, enabling rapid drug release and subsequent therapeutic action [69]. Hao et al. developed a tumor-targeted nanoplatform by conjugating RGD peptides to platinum nanozyme-loaded nanoparticles (Pt@RGD-NP), which co-delivered a GSH-responsive prodrug (PTX-SS-HPPH) for combinatorial chemo-PDT in bladder cancer. The prodrug design incorporated a disulfide linker between paclitaxel (PTX) and the photosensitizer HPPH, ensuring tumor-specific drug release via GSH-triggered cleavage [70]. Similarly, Jiang Guihua’s team engineered self-assembled nanoparticles (NPs) composed of a hydrophobic organic phototherapeutic agent (OPTA) and DSPE-SS-PEG2000. GSH-mediated disulfide bond disruption facilitated controlled drug release, significantly enhancing photodynamic (PDT) and photothermal (PTT) therapeutic efficacy in nasopharyngeal carcinoma models [71]. Yang et al. also conducted similar research (Figure 4) [72].

Figure 4.

Schematic illustration of GSH-responsive nanocarriers (siPLK1-NB NPs) enabling targeted photodynamic therapy in tumor tissues. NB-Br, brominated sulfur-substituted nile blue (a cationic photosensitizer); siPLK1, polo-like kinase 1 (PLK1) siRNA. Reprinted with permission from [72]. Copyright 2023 Wiley-VCH GmbH.

2.3.3. Enzyme responsiveness

Tumor tissues exhibit distinct enzymatic profiles compared to normal tissues, characterized by the dysregulated expression of various biological enzymes including matrix metalloproteinases (MMPs), hydrolases, lipases, and glycosidases. Leveraging these differential enzymatic signatures, enzyme-responsive nanocarriers have been engineered to enable tumor-specific delivery of therapeutic agents such as photosensitizers [73,74]. For instance, Hu et al. developed self-delivering nanoparticles (MA-pepA-Ce6 NPs) designed for MMP-2-mediated activation. MMP-2, a protease overexpressed in the tumor microenvironment, selectively cleaves these nanoparticles, triggering the release of both the photosensitizer chlorin e6 (Ce6) and the PD-L1 inhibitor metformin (MET). This dual-release mechanism synergistically enhances therapeutic efficacy in breast cancer models through combined PDT and immunotherapy [75].

2.3.4. ROS responsiveness

Tumor cells exhibit 10- to 100-fold higher intracellular ROS levels compared to normal cells [76]. This redox imbalance has been exploited to design ROS-responsive nanocarriers for tumor-targeted therapy [77]. Elevated tumoral ROS triggers both drug release and photoactivation, generating cytotoxic ROS bursts [78]. Concurrently, exogenous ROS produced during PDT induce photosensitizer liberation, establishing a self-amplifying therapeutic cycle [79]. Wan et al. developed NP-PDT@Reg, a self-assembled nanosystem co-delivering the photodynamic polymer PSP-Bodipy, a ROS-sensitive diselenide-based polymer (P1), and the multi-kinase inhibitor regorafenib. Upon 808 nm irradiation, photogenerated ROS mediate nanocarrier dissociation, facilitating regorafenib release to normalize tumor vasculature, alleviate hypoxia, and potentiate ROS production for immunogenic cell death (ICD) induction [80]. Analogously, Xu et al. engineered a ROS-responsive platform exhibiting spatiotemporal control over therapeutic payload release [81].

2.3.5. Other responsive carriers

Other intra-tumor tissue stimuli have also been widely investigated for nanocarriers to enhance tumor tissue targeting and control drug release, thereby enhancing PDT, including nucleic acid-responsive nanocarriers [82], H₂O₂-responsive nanocarriers [83], multiply-responsive nanocarriers (e.g., PH/ROS dual-responsive [84], PH/GSH dual-responsive [85], MMP-2/ROS dual-responsive [86], PH/ROS/MMP-2 triple response [87], light/ROS/GSH triple response [88]).

Tumor microenvironment-responsive carriers achieve intelligent release by sensing the unique physicochemical properties of tumor tissues, such as acidic pH, enzyme overexpression, and redox status. Comparatively, pH-responsive nanocarriers are relatively mature, leveraging the acidic tumor microenvironment to trigger photosensitizer release through a simple and universal mechanism. However, they often suffer from slow response rates and insufficient specificity, and may face premature release during circulation due to low pH (e.g., in lysosomes), which can be mitigated by protective designs such as multi-layer coating. Enzyme-responsive nanocarriers require optimization of carrier composition and structure for specific enzymes, offering high specificity. However, the heterogeneous distribution of enzyme activity in may lead to uneven release efficiency, affecting therapeutic consistency. Redox-responsive nanocarriers are sensitive to tumor metabolic characteristics, but their reaction chains may be disrupted by the complex tumor environment. Additionally, multi-responsive nanocarriers, which integrate multiple microenvironmental features, often exhibit superior synergistic effects and represent a promising direction for future improvements.

Overall, the design of tumor microenvironment-responsive nanocarriers must consider the heterogeneity within tumors and the complex delivery process in vivo. Optimization of stimulus-sensitive triggering mechanisms for controlled photosensitizer release, combined with practical considerations for material selection and functional modifications, is essential. Single-response designs are easier to implement but have limited performance, while multi-response synergistic designs better the complexity of the actual tumor microenvironment. From the perspective of in vivo performance, while enhancing therapeutic efficacy, it is crucial to control toxic side effects and immune or metabolic adverse reactions introduced by multifunctional modifications, ultimately achieving safe and efficient precision therapy.

3. Innovative photosensitizer development

Nanotechnology is utilized to overcome the shortcomings of traditional photosensitizers and enhance photosensitizer performance through strategies such as altering ROS generation, increasing ROS yield, and expanding the range of ROS action, thereby improving PDT efficacy.

3.1. Changing the ROS generation method

During PDT, photosensitizer (PS) molecules absorb photons upon irradiation with a specific wavelength, transitioning to an excited state. Subsequent relaxation to the ground state facilitates reactive oxygen species (ROS) generation. Type I PSs engage in electron or hydrogen atom transfer with adjacent molecules, yielding ROS such as superoxide anions (·O₂⁻) and hydroxyl radicals (·OH). In contrast, Type II PSs transfer energy to ground-state triplet oxygen (³O₂), producing cytotoxic singlet oxygen (¹O₂) [89]. Current clinical PSs predominantly follow the Type II mechanism, rendering their ROS production critically oxygen-dependent – a major limitation in hypoxic tumor microenvironment [90]. To address this, three strategies have emerged: (i) employing intrinsically oxygen-independent Type I PSs [91], (ii) engineering Type II PSs to exhibit Type I characteristics [92], or (iii) designing hybrid systems that synergize Type I and II pathways (Figure 5) [93]. Notable advances include: Xiong et al. developed a heterodimeric PS (NBSSe) by conjugating Type I (NBS) and Type II (NBSe) units, achieving efficient Type II-to-I conversion. Subsequent bovine serum albumin (BSA) encapsulation enhanced photostability and ·O₂⁻ generation via radical recycling, yielding tumor-targeted nanoparticles (BSA@NBSSe) with potent therapeutic efficacy [94]. Yue et al. rationally designed an organic PS (mBDP-PyBr) by optimizing triplet-state lifetime and intersystem crossing (ISC) efficiency. Formulated as DSPE-PEG-Biotin nanoparticles, mBDP-PyBr NPs demonstrated dual Type I/II ROS generation and superior tumor ablation under both normoxic and hypoxic conditions [95].

Figure 5.

Schematic illustration of the preparation procedure used to create CoPc-Mn/Ti3C2Tx-PEG/AS1411 and the in vivo PTT (type I and type II)/PDT/CDT synergistic antitumor mechanism. Reprinted with permission from [93]. Copyright American chemical society.

3.2. Increase ROS production

Φ∆ represents the quantum yield of cytotoxic singlet oxygen (¹O₂) generation by a photosensitizer upon light activation. For clinical-grade photosensitizers, Φ∆ typically ranges from 0.4 to 0.7, with higher values correlating to enhanced photoreactivity and therapeutic efficacy. For instance, Photofrin, a first-generation photosensitizer commonly used in PDT, demonstrates a Φ∆ of approximately 0.26–0.3 under physiological conditions, which is significantly lower than newer-generation agents like temoporfin (mTHPC) or chlorin e6, with Φ∆ values often exceeding 0.6. The yield of ROS during PDT can be effectively increased through the use of emerging nanomaterials, including nanoscale metal – organic frameworks, aggregation-induced luminescent materials, inorganic nanomaterials, metal nanoparticles, and semiconductor materials.

3.2.1. Nanoscale metal – organic framework

Nanoscale metal – organic frameworks (nMOFs) represent a class of porous crystalline materials characterized by three-dimensional networks formed through coordination between metal ions/clusters and organic ligands [96]. These architectures exhibit exceptional structural and compositional tunability, crystallinity, framework rigidity, high porosity, and biodegradability, making them ideal carriers for photosensitizers in PDT. The crystalline framework of nMOFs effectively mitigates photobleaching and self-quenching phenomena in encapsulated photosensitizers, thereby significantly enhancing PDT efficacy [97,98]. In a notable advancement, Zhao et al. engineered a theranostic nanoplatform (Fe-THBQ/SR) by encapsulating a STING agonist (SR-717) within an iron-tetrahydroxy-1,4-benzoquinone (Fe-THBQ) nMOF. This system leverages Fe-THBQ as a highly efficient second near-infrared window (NIR-II) photosensitizer. Under 1064 nm laser irradiation, Fe-THBQ/SR generates substantial reactive oxygen species (ROS), while simultaneously activating synergistic ferroptosis and STING-mediated immune responses for enhanced antitumor immunotherapy [99].

3.2.2. Aggregation-induced luminescent materials

Conventional photosensitizers possess a highly planar hydrophobic π-conjugated molecular framework, which promotes strong intermolecular interactions upon aggregation in aqueous solutions. This phenomenon triggers the aggregation-caused quenching (ACQ) effect, substantially compromising PDT efficacy [100]. In contrast, photosensitizers exhibiting aggregation-induced emission (AIE) characteristics demonstrate enhanced fluorescence intensity and superior reactive oxygen species (ROS) generation in the aggregated state compared to their conventional counterparts [101]. Notably, Yang et al. designed DTP-In, an AIE-active photosensitizer featuring a donor-acceptor (D-A) architecture. This compound spontaneously self-assembles in aqueous media to form cationic nanoaggregates, which exhibit mitochondrial targeting capability and significantly improved PDT performance (Figure 6) [102].

Figure 6.

Schematic illustration of donor and acceptor engineering of AIE PSs, and NIR-II FLI-guide photodynamic therapy. Reprinted with permission from [102]. Copyright 2024 Wiley-VCH GmbH.

3.2.3. Inorganic nanomaterials

In light of the superior properties of inorganic photosensitizers (PSs) over their organic counterparts – including exceptional photostability and enhanced tumor-targeting accumulation – significant research efforts have recently focused on developing inorganic nanomaterials as PSs for PDT [103,104]. Notably, inorganic nanomaterials such as CaO₂@CuS-MnO₂@HA [105], Au NPN6.5 [106], Tm₂O₃@PAA-RGD [107], and NIR-TADF nanoparticles [108] have demonstrated high PDT efficacy in the NIR-II window. Among these, layered double hydroxide (LDH)-based inorganic PSs have achieved groundbreaking progress in NIR-II PDT [109]. Yang et al. engineered defect-rich CoMo-LDH nanosheets via a metal (Zn) doping strategy, which modulated their electronic structures and bandgaps to facilitate efficient reactive oxygen species (ROS) generation under NIR-II laser irradiation. This approach significantly enhanced PDT outcomes, underscoring the potential of defect-engineered LDHs as advanced inorganic PSs [110].

3.2.4. Metal nanoparticles

Metallic nanoparticles (e.g., gold nanoparticles) exhibit localized surface plasmon resonance (LSPR), characterized by collective oscillations of conduction electrons under resonant light excitation, which results in enhanced light absorption and scattering [111]. The LSPR effect significantly improves photosensitizer excitation efficiency and quantum yields, thereby augmenting reactive oxygen species (ROS) production [112]. This mechanism has emerged as a prominent strategy to potentiate PDT efficacy [113,114]. For instance, Tian et al. engineered gold nanoparticles conjugated with the photosensitizer chlorin e6 (Ce6-Au NPs). These conjugates demonstrated superior synergistic PDT/photothermal therapy (PTT) performance, with markedly amplified photoactivity and ROS generation upon nanoparticle aggregation [115].

3.2.5. Semiconductor materials

Semiconductor materials have large π-conjugated structures, which result in large absorption coefficients, high photostability and excellent biocompatibility [116,117]. Semiconductor materials exhibit pronounced photocatalytic properties [118], generating electron-hole pairs upon photoexcitation. These charge carriers subsequently react with adsorbed oxygen and water molecules on the material surface to yield reactive oxygen species (ROS), including superoxide radicals (•O₂⁻) and hydroxyl radicals (•OH) [119]. Consequently, semiconductor-based photosensitizers demonstrate enhanced ROS quantum yields compared to conventional organic sensitizers [120]. Notably, Gao et al. [121] engineered a biomimetic nanocomposite (mUCC: UCNP@CeO₂/CuO@cancer cell membrane) featuring a heterojunction between n-type CeO₂ and p-type CuO semiconductors. Through a surface-growth methodology, this heterostructure was precisely anchored onto upconversion nanoparticles (UCNPs), forming an optimized core-shell architecture. Under near-infrared (NIR) irradiation, this design facilitates: (i) Enhanced light penetration depth via UCNP-mediated photon upconversion; (ii) Improved charge separation efficiency at the CeO₂/CuO interface; (iii) Synergistic amplification of photocatalytic ROS generation The engineered heterojunction not only augments the quantum yield of ROS production but also enables spatially controlled oxidative stress induction, demonstrating superior therapeutic efficacy in dynamic cancer therapy [121].

3.2.6. Quantum dots

Quantum dots (QDs), as semiconductor nanocrystals, exhibit superior optoelectronic characteristics, including broad excitation spectra, intense photoluminescence with high quantum yield, extended luminescence lifetime, and exceptional photostability [122]. These properties render them ideal candidates for PDT applications [123,124]. Liang et al. engineered manganese-doped graphene quantum dots (Mn-FGQDs) that demonstrate enhanced reactive oxygen species (ROS) generation capacity. This nanoplatform achieves lysosome-targeted damage, effectively inducing autophagy-associated tumor cell apoptosis and thereby augmenting PDT efficacy through precise subcellular organelle disruption [125].

3.3. Expanding the scope of ROS action

The wavelength of light determines its penetration capacity in biological tissues. In the visible light region, the depth of tissue penetration increases with increasing wavelength. Short wavelength light (e.g., blue and violet light, 400–500 nm) is strongly absorbed by pigments such as hemoglobin, limiting penetration depth to 1–2 mm, and is appropriate for treating superficial lesions. Medium wavelength light (green to red light, 500–700 nm) achieves greater penetration; for instance, red light (630 nm) can penetrate up to 1–2 cm. Long wavelength light (near-infrared [NIR], 700–1100 nm) exhibits minimal absorption and scattering, reaching a penetration depth of 2–3 cm, making it optimal for treating deeper tumors. Clinical PDT mainly uses short wavelengths of visible light, and its limited tissue penetration depth may lead to incomplete tumor killing or recurrence [126]. To overcome the attenuation of light in tissues, researchers have tried various methods to improve the excitation wavelength of photosensitizers, including upconversion nanoparticles, two-photon excitation, X-rays, and chemiluminescence.

3.3.1. Upconversion nanoparticles

Near-infrared (NIR) light, commonly designated as the “optical window” for biological tissues, exhibits significantly reduced absorption and scattering compared to UV-visible light. This property enables deeper tissue penetration while minimizing photodamage to healthy cells [127]. Upconversion nanoparticles (UCNPs) represent a class of specialized optical materials composed of a crystalline matrix (typically fluoride, oxide, or halide), doped with sensitizer and activator ions (lanthanides or actinides). Through the anti-Stokes process, UCNPs sequentially absorb multiple low-energy (long-wavelength) photons and emit higher-energy (short-wavelength) radiation. This unique photon conversion mechanism, involving NIR absorption followed by UV/visible emission, facilitates enhanced tissue penetration depth and subsequent photosensitizer activation for reactive oxygen species (ROS) generation [128]. Song et al. engineered a multifunctional DNA-UCNP complex capable of co-delivering CRISPR-Cas9, heme chloride, and protoporphyrin (PP) for synergistic cancer therapy. Upon 980 nm NIR irradiation (selected for optimal tissue penetration), the UCNP component emits 409 nm light to activate PP-mediated singlet oxygen (¹O₂) production, demonstrating potent cytotoxic effects against breast cancer cells (Figure 7) [129]. This work aligns with numerous studies demonstrating UCNP-mediated enhancement of PDT efficacy through improved light penetration [130–133].

Figure 7.

An RCA-based multifunctional DNA/UCNP complex for the controlled co-delivery of Cas9 RNP, hemin, and PP for synergistic photodynamic therapy. A) the molecular design and preparation of UCND. B) cellular uptake of UNCD and the process of synergistic photodynamic therapy. The Cas9 RNP was released via RNase H to cleave the target Nrf2 gene in nucleus. The downregulation of Nrf2 protein enhanced the cell sensitivity to PP-generated 1O2. UCNP, upconversion nanoparticles; UCNC, diblock DNA-bound UCNP; UCND, UCNC packed with multidrug-loaded ssDNA. Reprinted with permission from [129]. Copyright 2024 Wiley-VCH GmbH.

3.3.2. Two-photon PDTs

The photosensitizer employed in two-photon photodynamic therapy (TP-PDT) simultaneously absorbs two long-wavelength, low-energy photons (with wavelengths twice that of single-photon excitation), thereby substantially enhancing tissue penetration depth and therapeutic efficacy [134]. This approach has gained widespread adoption in oncological applications due to its superior spatial precision and reduced off-target effects [135,136]. Notably, Xu et al. developed an aggregation-induced emission (AIE)-active two-photon photosensitizer, MeTTh, which exhibits: a large two-photon absorption cross-section, NIR-II excitation capability,NIR-I emission and high reactive oxygen species (ROS) quantum yield. Through surface modification with transferrin, MeTTh nanoparticles achieved targeted delivery and highly efficient TP-PDT against orthotopic glioblastoma in vivo. Under 1040 nm NIR-II laser irradiation, these nanoparticles demonstrated significant tumor growth suppression while maintaining excellent biocompatibility [137].

3.3.3. X-ray PDT

X-ray-induced photodynamic therapy (X-PDT) is an emerging therapeutic modality that employs deeply penetrating X-rays as an external excitation source to generate cytotoxic singlet oxygen (¹O₂) for effective treatment of deep-seated tumors [138,139]. Conventional photosensitizers typically lack direct X-ray excitability and therefore require scintillators to mediate energy conversion from X-rays to visible light [140]. Gu et al. recently developed a biocompatible organic phosphorescent nanoscintillator, BPT-HOF@PEG, based on hydrogen-bonded organic frameworks (HOFs). This innovative material serves a dual function as both scintillator and photosensitizer, capable of directly absorbing X-ray energy and efficiently converting it into substantial quantities of ¹O₂, demonstrating potent therapeutic efficacy against hepatocellular carcinoma (HCC). The therapeutic mechanism involves two synergistic pathways: (1) X-ray-induced DNA damage in cancer cells and (2) PDT-mediated oxidative stress, collectively enhancing tumor cell eradication [141].

3.3.4. Chemiluminescence-based PDT

Chemiluminescence (CL), a light-emitting phenomenon resulting from chemical excitation during redox reactions without requiring external illumination, demonstrates exceptional sensitivity and specificity, particularly in energy transduction within tumor microenvironments, thereby establishing itself as a transformative modality for bioimaging and in vivo theranostics [142]. The implementation of CL-mediated PDT effectively addresses the photon attenuation challenge in deep tissues through intermolecular chemiluminescence resonance energy transfer (CRET), wherein chemical excitation energy is directionally transferred from CL donors to photosensitizing acceptors [143,144]. Li et al. engineered PFV-Luminol, an innovative chemiluminescent conjugated polymer comprising a poly(trifluorovinyl)vinyl (PFV) backbone (acceptor moiety) and iso-Luminol side chains (donor groups), which self-assemble into tumor-targeting nanoparticles (PFV-L@PEG-FA-NPs). This nanoplatform functions as an autonomous photosensitizer that generates both chemiluminescent signals and reactive oxygen species (ROS) through tumor-specific redox reactions, exhibiting superior tissue penetration depth for deep-seated tumor ablation [145]. Parallel advancements were achieved by Dai et al [146]. In addition, bioluminescence systems – a specialized CL variant – have been similarly exploited to circumvent PDT’s penetration limitations via luciferase-nanoparticle bioconjugates [147].

The tables below list some approved (Table 1) and clinically investigated (Table 2) nanotechnology-based photodynamic drugs. It can be observed that most of these drugs are focused on the treatment of esophageal cancer and head and neck cancer. These drugs also provide promising research directions for more disease.

Table 1.

Some globally approved photodynamic drugs. (the datas are sourced from ClinicalTrials.Gov.).

Manufacturer	Drug	Indication	Approval Country	Approval Year
QLT PhotoTherapeutics	Porfimer sodium (Photofrin)	Esophageal cancer, bladder cancer, lung cancer	Canada, the United States, Japan, European Union, etc	1993
QLT PhotoTherapeutics	Verteporfin (Visudyne)	Age-related macular degeneration	The United States, Canada	2000
Scotia QuantaNova	Temoprfin (Foscan)	Head and neck cancer	European Union	2001
Meiji Seika Pharma	Talaporfin (Laserphyrin)	Lung cancer, esophageal cancer	Japan	2004
Milelonge Pharma	hematoporphyrin derivative (HiPorfin)	Oral cavity, bladder, and other superficial cancers, port wine stains	China	2016
Shanghai Fudan-zhangjiang Bio-Pharmaceutical Co., Ltd.	Hemoporfin	port wine stains	China	2016
Steba Biotech	Padeliporfin (Tookad)	prostate cancer	European Union	2017
Rakuten Medical	Akalux (ADC drug)	Head and neck cancer	Japan	2020

Table 2.

Some photodynamic drugs under clinical trials. (the datas are sourced from ClinicalTrials.Gov.).

Manufacturer	Drug	Indication	Study Phase
Soligenix	Synthetic Hypericin (SGX301)	Cutaneous T-Cell Lymphoma	Phase 3 clinical trial
Luzitin SA	Redaporfin (LUZ11)	Head and neck cancer	Phase 2 clinical trial
Miravant Pharmaceuticals	Rostaporfin (Photrex)	Head and neck cancer	Phase 3 clinical trial
PCI Biotech AS	Fimaporfin	Cholangiocarcinoma	Phase 3 clinical trial
Shanghai Fudan-zhangjiang Bio-Pharmaceutical Co., Ltd.	Deuteporfin	Bladder cancer, cholangiocarcinoma	Phase 2 clinical trial
Fujian Longhua Pharmaceutical Co. Ltd	Photocyanine	Skin cancer, esophageal cancer	Phase 2 clinical trial
Qinglong High-tech Co., Ltd.	Sinoporphyrin sodium	Esophageal cancer	Phase 3 clinical trial
Zhejiang Hisun Pharmaceutical Co. Ltd.	HPPH	Esophageal cancer	Phase 1 clinical trial

4. Improvement of the tumor microenvironment

The inherent characteristics of the tumor microenvironment (TME) that severely impair the efficacy of PDT include (1) hypoxia that reduces the efficiency of ROS generation by type II photosensitizers; (2) a robust antioxidant system capable of scavenging ROS; (3) limitations on the penetration of photosensitizers and O₂, such as a dense extracellular matrix (ECM) and a high pressure of interstitial fluid; and (4) an immunosuppressive microenvironment that hinders PDT-induced anti-tumor immune response. Improving the tumor microenvironment using nanotechnology is one of the effective strategies to enhance the efficacy of PDT.

4.1. Amelioration of hypoxia

Tumor hypoxia is due to the rapid proliferation of tumor cells that consume large amounts of oxygen as well as abnormal tumor vascular structures that limit oxygen supply [148]. Hypoxia usually limits ROS generation and induces PDT resistance, leading to poor clinical prognosis in many malignant tumors [149,150]. To ameliorate tumor hypoxia, several strategies have been developed, including transport of oxygen via oxygen-carrying carriers [151], in situ oxygen-producing mechanisms [152], reduction of tumor oxygen consumption [153], and normalization of tumor vasculature [154].

4.1.1. Oxygen-carrying carriers

The direct administration of oxygen via highly oxygen-philic materials represents a promising strategy to augment tumor oxygenation and alleviate hypoxic conditions. Perfluorocarbons (PFCs) – fully fluorinated hydrocarbon analogs – serve as key constituents of artificial blood substitutes due to their exceptional oxygen-dissolving capacity and minimal intermolecular interactions [155]. Numerous PFC-based nanoplatforms have been engineered to facilitate oxygen transport and mitigate tumor hypoxia [156]. Zhang et al. developed a multifunctional nanocomposite, PSPP-Au980-D, by encapsulating PFC and silicon phthalocyanine (SiPc) within functionalized bilayer polymers, further integrating gold nanorods (Au NRs) and doxorubicin (DOX). Upon 980 nm laser irradiation, the Au NRs mediated photothermal therapy (PTT) while triggering oxygen and DOX release from the PFC reservoir. Subsequent 680 nm laser exposure activated SiPc to generate singlet oxygen (¹O₂), enabling PDT. This synergistic combination of PDT, PTT, and chemotherapy significantly enhanced therapeutic efficacy against hypoxic tumors [157].

Hemoglobin (Hb), another widely utilized oxygen carrier, facilitates physiological oxygen transport via reversible oxygen binding. However, free Hb exhibits poor plasma stability and rapid clearance, necessitating nanotechnological interventions to optimize its pharmacokinetics [158]. Lee et al. engineered DOX@HPBC, a protein nanocluster comprising Hb, chlorin e6 (Ce6), and biotinylated polyethylene glycol with surface-adsorbed DOX. This formulation effectively normalized tumor hypoxia markers (HIF-1α and MDR1) and potentiated the combined effects of chemotherapy and PDT in cervical cancer models [159].

Beyond PFCs and Hb, alternative oxygen-delivery platforms include metal-organic frameworks (MOFs) [160], gas vesicles (GVs) [161,162], and cytomimetic nanovesicles (CBVs) [163,164]. These systems collectively address tumor hypoxia and amplify the therapeutic outcomes of PDT.

4.1.2. In situ oxygen production

In situ oxygen generation represents the most direct and efficacious approach to ameliorate tumor hypoxia, offering superior safety profiles by circumventing oxygen leakage risks inherent in exogenous delivery systems [165]. Current methodologies for intratumoral oxygen production primarily encompass catalytic decomposition of hydrogen peroxide (H₂O₂) [166], water (H₂O) catabolism [167], and photosynthetic oxygen generation by engineered microorganisms [168]. The tumor microenvironment’s characteristic metabolic aberrations result in elevated H₂O₂ concentrations, which can be enzymatically cleaved into oxygen and water by endogenous catalase (CAT), a ubiquitous oxidoreductase [155]. This biochemical principle has been exploited in numerous nanotherapeutic platforms designed to potentiate PDT efficacy [169]. For instance, Huang et al. developed an ultra-acid-sensitive polymeric nanocomplex incorporating CAT and human serum albumin (HSA), where HSA serves to mitigate immunogenicity while the pH-responsive polymer ensures lysosomal escape and targeted CAT delivery. This system demonstrated significant tumor accumulation and hypoxia alleviation in breast cancer models, substantially enhancing PDT outcomes [170]. Manganese dioxide (MnO2) and other metallic nanomaterials have emerged as potent inorganic catalysts for the decomposition of H₂O₂ into O₂ and H₂O [171]. Bai et al. reported a multifunctional “photodynamic gel-bomb” platform (DCM@OPR) comprising chlorin e6 (Ce6), MnO₂ nanoparticles, and doxorubicin (DOX) within a calcium-crosslinked alginate matrix. This system not only improved oxygen supply for PDT but also synergistically activated the cGAS/STING pathway through Mn2⁺-DOX coordination, demonstrating profound antitumor effects in breast cancer models (Figure 8) [172]. Alternative oxygen-generating compounds including calcium peroxide (CaO₂) and magnesium peroxide (MgO₂) have shown promise through their tumor-selective decomposition into H₂O₂ and subsequent oxygen release [173,174].

Figure 8.

Schematic illustration of photodynamic gel-bombs for enhanced tumor deep penetration and synergistic therapies [172].

Water splitting represents another innovative oxygen-generation strategy [175], exemplified by Yin et al.‘s development of two-dimensional C₃N₄-MnO₂ nanodrug precursors that undergo tumor-specific transformation into single-atom catalysts (C₃N₄-Mn SACs) in response to glutathione (GSH) overexpression. These catalysts facilitate photolytic water splitting under 660 nm irradiation, generating hydroxyl radicals while ameliorating hypoxia [176].

Photosynthetic microorganisms have been engineered as biological oxygen pumps, leveraging their chlorophyll-based photosynthetic machinery to elevate intratumoral oxygen levels [177], such as Chlorella [178], Cyanobacteria [179], and Spirulina [180]. A notable advancement in this domain is the engineered cyanobacteria-based nanosystem (ECyano@MnO₂) developed by Liu et al., which simultaneously produces the photosensitizer 5-aminolevulinic acid (5-ALA) and oxygen under 640 nm illumination while MnO₂ decomposition activates dendritic cell-mediated antitumor immunity through Mn²⁺ release. These diverse oxygen-generation strategies collectively address the fundamental limitation of tumor hypoxia in PDT, each offering unique advantages in terms of spatiotemporal control, biocompatibility, and potential for combination therapies [181].

4.1.3. Reduction of oxygen consumption

Modulating the aberrant oxygen consumption of tumor cells represents a promising strategy to alleviate tumor hypoxia. Mitochondrial oxidative phosphorylation (OXPHOS), as the predominant oxygen-utilizing process in cellular respiration, serves as a critical therapeutic target [182]. Pharmacological inhibition of OXPHOS in neoplastic cells attenuates oxygen demand, thereby ameliorating hypoxia and potentiating PDT efficacy [183]. Diverse mitochondrial respiratory chain inhibitors have been investigated, including atovaquone (ATO) [184], papaverine (PPV) [185], 3-bromopyruvate (3-BP) [186], tamoxifen [187], metformin (MET) [188], nitric oxide (NO) [189], lonidamine [190], and 7-amino carboxycoumarins-2 [191]. Mechanistically, PPV, MET, and tamoxifen suppress oxygen consumption via electron transport chain (ETC) complex I inhibition, whereas ATO and NO target complex III, and lonidamine inhibits complex II.

Nanocarrier-mediated co-delivery of photosensitizers and OXPHOS inhibitors synergistically reduces tumor oxygen demand, enhancing PDT outcomes. Huang et al. engineered a multifunctional supramolecular nanoplatform (SNP@Ato) via host-guest interactions between sulfhydryl-conjugated camptothecin/azobenzene (Azo-TK-CPT) and β-cyclodextrin-functionalized tetraphenylporphyrin (TPP-CD4), coupled with Ato self-assembly. Hypoxia-activated azoreductase cleaved the azobenzene moiety in SNP@Ato, triggering Ato release to inhibit mitochondrial respiration and mitigate local hypoxia. In vivo and ex vivo studies demonstrated significant PDT enhancement in hypoxic tumors using this system [192].

4.1.4. Normalization of blood vessels

The hypoxic microenvironment in tumors arises, in part, from aberrant tumor vasculature characterized by morphological irregularities, excessive tortuosity, elevated vascular permeability, and impaired blood flow dynamics. These vascular abnormalities result in perfusion defects that compromise oxygen delivery and limit the distribution of therapeutic agents. Furthermore, pathological vascular features, including enhanced permeability, facilitate plasma protein extravasation, interstitial fluid accumulation within the tumor stroma, and consequent elevation of tumor interstitial fluid pressure (TIFP), collectively creating a formidable barrier to oxygen diffusion and photosensitizer penetration that significantly impedes therapeutic efficacy [193]. Current vascular normalization strategies can be categorized into three principal approaches: (1) Conventional anti-angiogenic agents, exemplified by multikinase inhibitors (e.g., Regorafenib) [80], multi-targeted tyrosine kinase inhibitors (e.g., Lenvatinib) [194], and EGFR inhibitors (e.g., Erlotinib) [195]. Jiang et al. engineered a dual-nucleus-satellite nanostructure incorporating the photosensitizer Rose Bengal, the scintillator calcium fluoride (CaF₂), and the anti-angiogenic compound Sunitinib, demonstrating that localized Sunitinib release following low-dose X-ray irradiation significantly ameliorated tumor hypoxia and potentiated X-ray-induced photodynamic therapy (X-PDT) efficacy through vascular normalization [196]. (2) Angiogenesis-modulating compounds including: (i) oxygen species that activate the TRPV4-endothelial nitric oxide synthase (TRPV4-eNOS) signaling cascade [197], (ii) the glucocorticoid dexamethasone [198], and (iii) histidine-rich glycoproteins (HRGs) that interact with myosin to modulate vascular architecture [199]. (3) Gaseous therapeutics including carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H₂S), which remodel the tumor microenvironment through vascular improvement and normalization [200]. Wang et al. developed ROS-responsive nanoliposomes co-loaded with the photosensitizer chlorin e6 (Ce6), the NO precursor L-arginine, and the NRF2 inhibitor ML385. Within the tumor microenvironment, H₂O₂-mediated oxidation of L-arginine generates NO, which promotes vascular normalization, ameliorates hypoxia, and enhances PDT efficacy. Notably, NO exerts direct cytotoxic effects on malignant cells and reacts with reactive oxygen species to form peroxynitrite (ONOO-), a highly reactive nitrogen species with potent antitumor activity, thereby achieving synergistic therapeutic outcomes in cholangiocarcinoma through combined photodynamic and gas therapy [78].

4.2. Antioxidation

Tumor cells exhibit enhanced antioxidant capacity through the consumption of substantial reactive oxygen species (ROS), thereby maintaining viability under elevated oxidative stress conditions that would otherwise compromise the efficacy of ROS-mediated PDT [201]. Consequently, targeting the multifaceted antioxidant defense systems of tumors represents a promising strategy to potentiate PDT outcomes [202]. These defense mechanisms primarily comprise the glutathione (GSH) and thioredoxin (TRX) systems [203], with tumor GSH concentrations exceeding normal cellular levels by orders of magnitude. The TRX system, consisting of thioredoxin (TRX) and thioredoxin reductase (TRXR), directly scavenges singlet oxygen and hydroxyl radicals, while TRXR regenerates oxidized TRX [204]. Xiong et al. developed a composite nanomedicine (Phy@HES-IR) that simultaneously inhibits both GSH and TRX pathways through distinct mechanisms: pheophorbide methyl ester (Phy) suppresses 6-phosphogluconate dehydrogenase (6-PGD) to reduce NADPH-dependent GSH synthesis, while IR820 serves dual functions as both photosensitizer and TRXR inhibitor (Figure 9) [205].

Figure 9.

Schematic illustration of multistage redox regulation strategy for photodynamic immunotherapy. Reprinted with permission from [205]. Copyright 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

The tumor antioxidant repertoire further encompasses enzymatic defenses including superoxide dismutase (SOD), catalase (CAT), peroxiredoxins (PRDX), and heme oxygenase-1 (HO-1) [76]. Strategic inhibition of these enzymes has demonstrated significant potential for PDT enhancement [206]. Zou et al. engineered a pH/redox-responsive nanoplatform (ZnPP@FQOS) that simultaneously modulates cancer-associated fibroblasts (CAFs) and downregulates HO-1, thereby compromising the cellular antioxidant stress capacity and sensitizing tumors to oxidative damage [85]. Beyond enzymatic defenses, anti-apoptotic proteins like Bcl-2 contribute to oxidative stress resistance through cell survival mechanisms, with their inhibition shown to amplify PDT-induced oxidative damage [207].

Transcriptional regulation of antioxidant genes represents another critical layer of control, primarily mediated through the Keap1-Nrf2 axis. Under basal conditions, nuclear factor erythroid 2-related factor 2 (Nrf2) undergoes Keap1-dependent ubiquitination and proteasomal degradation. Oxidative stress triggers cysteine modification of Keap1, stabilizing Nrf2 to induce expression of antioxidant genes including NAD(P)H quinone oxidoreductase 1 (NQO1), HO-1, and TRXR [208]. Bao et al. developed a multifunctional nanoparticle (OPFV-SnMP@GE11) that precisely modulates the Keap1-Nrf2 pathway to elevate intracellular ROS levels, thereby synergizing with PDT for enhanced antitumor efficacy [209].

4.3. Remodeling the extracellular matrix

The pathological characteristics of tumor microenvironments – including aberrant vascularization, dense extracellular matrix (ECM) deposition, and elevated interstitial fluid pressure – severely restrict the penetration efficiency of photosensitizers and molecular oxygen, thereby compromising PDT efficacy. To address these limitations, ECM remodeling strategies have emerged as a promising approach: (1) disruption of the fibrotic niche via enzymatic degradation of structural ECM components (e.g., collagenase or hyaluronidase-mediated hydrolysis) [210,211]; and (2) modulation of stromal cell activity through functional silencing or suppression of ECM secretory pathways to inhibit fibrotic matrix deposition [212–214]. In a notable advancement, Xu et al. engineered a biomimetic nanosystem (M1@PAP) comprising poly-L-arginine (Arg9)-conjugated photosensitizer PPA self-assembled into cationic nanoparticles, which were subsequently complexed with siPD-L1 via electrostatic interactions and enveloped by M1 macrophage membranes. Upon photoactivation, this platform generated cytotoxic nitric oxide (NO) that simultaneously degraded ECM constituents and suppressed fibroblast activation, thereby normalizing tumor stroma architecture. This dual mechanism enhanced both nanocarrier permeation and immune cell infiltration, ultimately potentiating PDT outcomes in pancreatic ductal adenocarcinoma (PDAC) models (Figure 10) [215].

Figure 10.

Schematic illustration of the M1@PAP preparation, and photodynamic therapy and immune activation mechanism. Reprinted with permission from [215]. Copyright 2025 American chemical society.

4.4. Immunosuppression

PDT not only kills tumor cells directly, but also triggers local inflammation and activates the body’s immune system, resulting in a long-lasting anti-tumor immune effect. In this process, tumor-associated antigens (TAA) released by damaged tumor cells promote the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T cells (CTLs) into the tumor microenvironment (TME), resulting in immune activation and a powerful tumor killing effect [216]. However, in most cases, the immunosuppressive tumor microenvironment (TME) greatly limits the pattern and level of T-cell infiltration and activation, leading to failure of immune activation or impairing the strength of subsequent immune responses [217]. Therefore, combining PDT with TME immunomodulation is necessary for enhancing anti-tumor immune responses.

4.4.1. Regulation of immune cell populations

Immunosuppressive cells within the tumor microenvironment (TME), including regulatory T cells (Tregs), M2-polarized tumor-associated macrophages (M2-TAMs), and myeloid-derived suppressor cells (MDSCs), exert potent inhibition of antitumor immune responses through multifaceted mechanisms. These encompass secretion of immunosuppressive cytokines (IL-10, TGF-β, IL-6, IL-28, IL-35) [218,219], expression of immune checkpoint molecules (e.g., PD-L1), and production of immunosuppressive enzymes (matrix metalloproteinases, inducible nitric oxide synthase, arginase 1) [220].

Consequently, targeted depletion of these immunosuppressive populations can significantly potentiate phototherapy-induced antitumor immunity [221]. He et al. developed an innovative pH-responsive supramolecular photodynamic nanoparticle (DACss) based on β-cyclodextrin (CD), co-loaded with the photosensitizer chlorin e6 (Ce6) and the immunomodulator dimethylcurcumin (DMC). The acid-labile β-carboxamide linkage in DMC-CD undergoes hydrolysis in the acidic TME, enabling localized release of DMC to suppress Treg differentiation and thereby ameliorate the immunosuppressive TME [222]. Another promising approach involves reprogramming TAMs from protumor M2 phenotype to antitumor M1 phenotype [223]. Tong et al. engineered a multifunctional PROTAC-PDT nanoplatform (dBET6@CFMPD) that undergoes MMP-2-mediated morphological transformation from spherical nanoparticles to nanofibers, releasing the PROTAC molecule dBET6 to simultaneously downregulate PD-L1 expression, enhance T cell infiltration, and promote M2-to-M1 TAM repolarization [224]. Furthermore, current therapeutic strategies targeting MDSCs encompass three principal modalities: direct depletion, functional inhibition, and blockade of recruitment pathways [225,226].

4.4.2. Immune checkpoint blockade

The immune checkpoint molecules primarily comprise cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor 1 and its ligands (PD-1/PD-L1), and indoleamine 2,3-dioxygenase 1 (IDO-1). CTLA-4, a transmembrane receptor expressed on T cells, mediates inhibitory signaling upon binding to B7 family ligands, thereby suppressing T cell proliferation and activation. PD-1, a critical immunosuppressive transmembrane protein on T cells, induces T cell apoptosis and inhibits proliferation upon interaction with tumor cell-expressed PD-L1, exacerbating immunosuppression and facilitating tumor immune evasion [227]. IDO-1, expressed in tumor cells and antigen-presenting cells (e.g., macrophages and dendritic cells), functions as a key catabolic enzyme of tryptophan, elevating the kynurenine-to-tryptophan ratio to potentiate immunosuppressive tolerance and promote regulatory T cell (Treg) expansion and infiltration [228].

These mechanistic insights have driven the development of diverse immune checkpoint-blocking antibodies and small molecule inhibitors. Combinatorial approaches incorporating immune checkpoint inhibitors represent an effective strategy to augment PDT-induced systemic antitumor immunity [229–231]. Notably, Li et al. engineered a hairpin tetrahedral DNA nanostructure (H-TDN) functionalized with the photosensitizer pyropheophorbide-a (Ppa) to construct a single-atom nanozyme (PCFP@H-TDN). This system exhibits catalase (CAT)-like and peroxidase (POD)-mimetic activities, catalyzing endogenous H₂O₂ decomposition into O₂ to alleviate tumor hypoxia while simultaneously generating reactive oxygen species (ROS). The H-TDN outer layer demonstrates dual immunomodulatory capabilities: (1) competitively inhibiting PD-1/PD-L1 interaction and (2) silencing PD-L1 protein expression. By synergizing potent ROS generation with immune checkpoint blockade, PCFP@H-TDN induces immunogenic cell death, releasing tumor antigens while promoting immune cell infiltration, activation, and proliferation within the tumor microenvironment (Figure 11) [232].

Figure 11.

(A) Schematic diagram of the stepwise preparation process of PCFP@H-TDN. (B) Anti-tumor mechanism of H-TDN with the dual functions of PD-L1/PD-1 recognition blockade and PD-L1 silencing. (C) Internalization and subsequent cascade catalytic generation of abundant O2 by single-atom nanozymes in tumor cells to enhance PDT and induce ICD. Reprinted with permission from [232]. Copyright 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

4.4.3. Immune adjuvants

The co-administration of immunostimulatory adjuvants potentiates immune system activation, significantly augmenting PDT-elicited antitumor immunity. Immunological adjuvants constitute a class of biologically active molecules that amplify antigen-specific immune responses through distinct mechanistic pathways: (1) Toll-like receptor (TLR)-targeting adjuvants, wherein TLRs – a family of pattern recognition receptors predominantly expressed on dendritic cells (DCs), natural killer (NK) cells, and macrophages – recognize conserved molecular motifs including pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), such as lipopolysaccharides and heat shock proteins, thereby initiating inflammatory cascades that bridge innate and adaptive immunity. TLRs engagement trigger DC maturation, enhances antigen presentation capacity, and promotes CD4⁺ T cells polarization into Th1, Th2, and Th17 subsets while concurrently suppressing regulatory T cells (Tregs) activity. (2) Alternative adjuvant formulations including aluminum salts (alum), which activate the NALP3 inflammasome to induce caspase-1-dependent interleukin-1β (IL-1β) secretion and innate immune stimulation. Additionally, naturally derived exosomes – nanometer-scale extracellular vesicles – exhibit intrinsic adjuvant properties through cell type-specific antigen presentation mechanisms; for instance, tumor-derived or DC-secreted exosomes can prime antitumor immune responses [233]. Notably, Li et al. developed chondroitin sulfate-based nanoplatforms co-delivering chlorin e6 photosensitizers and retinoic acid to disrupt Golgi apparatus function while incorporating CpG oligodeoxynucleotides as potent TLR9 agonists to promote DC maturation, thereby synergistically enhancing PDT-induced immunogenic cell death and subsequent antitumor immunity [234].

5. Conclusions

While advanced nanotechnology show remarkable potential in enhancing PDT, several critical challenges remain unaddressed. The primary concern lies in the incomplete validation of biocompatibility and safety profiles for numerous emerging nanomaterials, including in vivo distribution, metabolism, and long-term toxicity. Consequently, researchers should prioritize FDA-approved materials for nanocarriers preparation, or conduct comprehensive pharmacotoxicological analyses to optimize safety and efficacy. Of particular concern is the potential organ damage resulting from nanoparticle leakage during circulation and accumulation in healthy tissues. A second major challenge involves the industrial scalability of laboratory-developed nanoparticles, which necessitates the development of high-throughput processes. With the advancement of various technologies, researchers are increasingly using combinations of multiple nanomaterials and therapeutic modalities to design drug delivery systems. Although the multi-material composite design can synergistically address multiple deficiencies and improve the anti-tumor effect of PDT, it faces synthesis complexity, low yield, unclear toxicity, and clinical translation barriers. Therefore, researchers should examine and understand each step and influencing factor of PDT, rationally design strategies to improve efficacy, and utilize the synergistic effect of multi-materials and multi-technologies instead of blindly combining and superimposing them.

6. Future perspective

In a word, nanotechnology-enhanced PDT faces a dual development challenge. While nanomaterials and technologies offer promising strategies to improve anti-tumor effects of PDT, most existing technologies remain at the proof-of-concept stage. The core contradiction focuses on three key bottlenecks:the three bottlenecks of scalable production, biosafety assessment and translational pathways, emphasizing the need for a systematic analysis of PDT’s various aspects and the establishment of a dynamic balance between innovative design and clinical needs. Moving forward, priority should be given to establishing standardized evaluation protocols for nanomaterial biocompatibility (including the development of standardized in vitro and in vivo models for assessing nanomaterial safety in the context of PDT) and streamlined pathways for clinical implementation (focusing on monolithic nanoparticle designs with inherent multifunctionalit to simplify scale-up and regulatory approval). Simultaneously, it is necessary to strengthen our fundamental understanding of PDT (e.g., novel NIR-II photosensitizers represent a promising direction for deep-tissue PDT) while integrating complementary therapies (e.g., chemotherapy, gas therapy) [235,236], fostering cross-disciplinary collaborations (e.g., epigenetics, immunology) [237], and implementing consistent therapeutic standards (e.g., photosensitizer dosage, light wavelength, power, and duration). These initiatives will be crucial in facilitating the successful transition of innovative laboratory findings into practical clinical applications.

Funding Statement

This work was supported by the National Natural Science Foundation of China [No 82473852-Lihua Luo].

Article highlights

• Systematicallyintroduces the mechanisms, advantages, and limitations ofphotodynamic therapy (PDT).

• Comprehensivelyreviews strategies to enhance nanotechnology-mediated PDT, focusing on its operational processes.

• Summarizesnanotechnology-based strategies for targeted delivery ofphotosensitizers to subcellular organelles and tumor cells.

• Providesan in-depth overview of stimuli-responsive nanocarriers designsactivated by pH, redox, and specific enzymes in the tumormicroenvironment (TME) to realize precise photosensitizer release.

• Focuseson strategies utilizing novel nanomaterials and technologies toenhance ROS generation and tissue penetration depth ofphotosensitizers.

• Summarizesapproaches to remodle the tumor microenvironment by alleviatinghypoxia and immunosuppression to optimize PDT efficacy.

• Highlightsthe nanotechnology-based photodynamic drugs that have been approvedor are in clinical trials，offeringguidance for clinical translation.

• Outlinescritical challenges in nanotechnology-enhanced PDT and proposesforward-looking strategies to address translational challenges.

Authors’ contributions

YanhanMo: Writing – Original Draft Preparation, Writing – Review & Editing. Xu Liu: Writing – Original Draft Preparation. Jian You: Software, Funding Acquisition. Lihua Luo: Supervision, Investigation,Funding Acquisition. All the authors have approved the manuscript andagree with submission to your esteemed journal.

Disclosure statement

The authors have no relevant affiliations or financial involvement withany organization or entity with a financial interest in or financialconflict with the subject matter or materials discussed in themanuscript. This includes employment, consultancies, honoraria, stockownership or options, expert testimony, grants or patents received orpending, or royalties.

Writing assistance

Nowriting assistance was utilized in the production of this manuscript.

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Peerreviewers on this manuscript have no relevant financial or otherrelationships to disclose.