The complexity and heterogeneity of malignant tumors are major contributors to their high mortality rate, making cancer treatment a critical challenge in nanomedicine and life sciences (Bian et al., 2024; Cantallops Vilà et al., 2024). Various approaches have been developed, including surgery, chemotherapy, radiotherapy, photodynamic therapy (PDT), immunotherapy, and gene therapy (Cortés-Guiral et al., 2021; Pan Y. et al., 2022; Xie R. et al., 2023; Qian et al., 2024). Among these, PDT has gained significant attention due to its spatiotemporal precision, low cost, ease of application, and minimal toxic side effects (Li et al., 2020; Di Bartolomeo et al., 2022). Notably, unlike conventional therapies, PDT rarely causes drug resistance or severe adverse effects (Sun B. et al., 2023; Hua et al., 2024). PDT relies on three essential components: a photosensitizer, light, and oxygen (O₂) (Kolarikova et al., 2023; Wang et al., 2023). Upon absorption of light at specific wavelengths (typically matching its absorption spectrum), the photosensitizer undergoes a transition from the ground state to an excited singlet state (S₁), followed by intersystem crossing to form a longer-lived triplet state (T₁) (Fay and Limmer, 2024; Kim et al., 2024). This T₁ species then mediates the two primary mechanisms of PDT (Figure 1A). Type II PDT is defined by energy transfer from the triplet-state photosensitizer to ground-state molecular oxygen (³O₂), which is converted into highly cytotoxic singlet oxygen (¹O₂) (Shigemitsu et al., 2022; Yu L. et al., 2024). This process is strictly O₂-dependent, as ¹O₂ generation directly relies on the availability of O₂, and the short half-life of ¹O₂ limits its diffusion to a narrow region around the photosensitizer. In contrast, Type I PDT is characterized by relatively low O₂ dependence, enabling it to retain efficacy even in hypoxic tumor regions. It operates through a distinct pathway where the excited photosensitizer, typically in its T₁, undergoes electron transfer or hydrogen atom abstraction reactions with biological substrates, such as amino acids, lipids, or nucleic acids, in the tumor microenvironment. This substrate-mediated interaction leads to the generation of a suite of reactive oxygen species (ROS), including superoxide anion radicals (•O₂ ⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (•OH) (Wen et al., 2022; Zhen et al., 2025). Despite these differences in ROS generation mechanisms and oxygen requirements, both Type I and Type II PDT culminate in elevated oxidative stress in the tumor microenvironment, ultimately inducing cancer cell death (Yu Y. et al., 2023; Zhang et al., 2023d).

However, we must confront an undeniable fact: despite the increasing number of studies on PDT-based anti-tumor treatments in recent years, several critical issues still need to be addressed (Sun et al., 2022). One of the most prominent challenges is the extremely short half-life (0.03–0.18 µs) and limited action range (0.01–0.02 µm) of ¹O₂ generated by photosensitizers (Moan and Berg, 1991; Niedre et al., 2002). As a result, the oxidative effects of PDT-induced ROS are largely confined to areas in close proximity to the photosensitizer (Austin et al., 2025). To overcome this limitation, investigating the mechanism of PDT-induced immunogenic cell death (ICD) has emerged as a potentially effective strategy (Zhang et al., 2022b; Zhang T. et al., 2023). Nevertheless, an even more promising approach may lie in further enhancing the targeting capability of photosensitizer-based nanoplatforms, particularly their ability to selectively target various subcellular organelles (Sun et al., 2024). Achieving precise subcellular localization enables targeted disruption at critical sites, triggering a systemic effect that can ultimately lead to different modes of cancer cell death, including apoptosis, necrosis, or pyroptosis (Tong et al., 2024; Wang B. et al., 2024).

Cells are the fundamental units of life, and their normal metabolism is essential for maintaining health (Finley, 2023; Sun et al., 2025). Disruptions in cellular metabolism can lead to various diseases (Plikus et al., 2021; Lee et al., 2024). Such metabolic processes rely heavily on the coordinated function and communication among intracellular organelles (König and McBride, 2024; Zimmermann et al., 2024). Common organelles include mitochondria, lysosomes, endoplasmic reticulum (ER), Golgi apparatus, endosomes, and centrosomes, each playing a distinct role in cellular function (Bornens, 2021; Celik et al., 2023; Ebner et al., 2023; Meyer and Kravic, 2024; Sun S. et al., 2024). The cell membrane, as a phospholipid bilayer structure, plays a critical role in maintaining the separation and homeostasis between the intracellular and extracellular environments (Zhu X. et al., 2024). It is particularly susceptible to oxidative attack by ROS, leading to the generation of abundant lipid peroxidation (LPO) products (Pope and Dixon, 2023; Zhu et al., 2023). This not only exacerbates membrane damage but also provides a mechanistic basis for the synergistic enhancement of PDT with ferroptosis (Pan W. et al., 2022; Chen et al., 2024). Mitochondria generate adenosine triphosphate (ATP) through aerobic respiration, providing energy for cellular activities (Dong et al., 2023; Granath-Panelo and Kajimura, 2024). Upon exposure to ROS, mitochondria experience disruption of membrane potential and functional impairment, leading to reduced O₂ consumption (Cho and Kim, 2024). This creates a favorable environment for O₂-dependent PDT to generate increased levels of ROS, thereby enhancing therapeutic efficacy (Cen et al., 2023). Lysosomes degrade unwanted cellular materials via hydrolytic enzymes (Settembre and Perera, 2024; Sweet et al., 2025). Following ROS-induced damage, the permeability of the lysosomal membrane is altered, leading to the release of intracellular cathepsins that induce cell death. This mechanism opens up new avenues for cancer therapy (Yu Q. et al., 2023; Chen F. et al., 2025). The ER is crucial for the synthesis and transport of proteins and lipids, while the Golgi apparatus modifies, sorts, and transports proteins for secretion or delivery to other organelles (Weigel et al., 2021; Tang and Ginsburg, 2023). ROS-induced oxidative stress in the ER and the reduction of immunosuppressive factor secretion by the Golgi apparatus caused by ROS both provide new opportunities and mechanistic insights for enhanced PDT (Liu M. et al., 2022; Zhang X. et al., 2022). Given these critical roles, maintaining the structural and functional integrity of organelles is vital for cell survival (Yao et al., 2021; Harapas et al., 2022). Conversely, disrupting organelle function-such as by damaging membranes, altering membrane potential, or releasing destructive enzymes-can impair cellular metabolism and trigger programmed cell death, making organelles promising targets for therapeutic interventions (Šlachtová et al., 2023; Soukar et al., 2025).

Several reviews have summarized strategies for targeting specific organelles through material design to treat diseases, primarily focusing on the development of targeting agents (Yang et al., 2022; Shao et al., 2023; Ying et al., 2023; Hong et al., 2024). In contrast, this review highlights the structural features required for designing photosensitizers that target different organelles (Figure 1B). We also evaluate which organelles are most effective targets in PDT, particularly in overcoming challenges such as tumor hypoxia, drug resistance, metastasis, and recurrence. By analyzing current studies on organelle-targeted PDT, we aim to deepen the understanding of PDT’s mechanisms in inhibiting tumor growth and provide insights for its future clinical application.

Animal cells contain a variety of structurally and functionally distinct organelles that work in concert to maintain cellular homeostasis. These organelles not only carry out essential biological processes but also serve as potential targets for therapeutic interventions, including PDT (Liu X. et al., 2022; Xu Y. et al., 2025). Targeting specific organelles with photosensitizers can enhance PDT efficacy by inducing localized damage and activating cell death pathways (Chai et al., 2022). Below is an overview of key organelles and their functional roles relevant to PDT (Table 1).

The cell membrane acts as a selective barrier, regulating nutrient uptake and waste removal. It also plays a central role in signal transduction and intercellular communication (Bijonowski et al., 2025). Damage to the cell membrane via PDT can disrupt ion balance and trigger apoptosis (Fang R. H. et al., 2023). Moreover, it is well known that the therapeutic efficacy of PDT is not only limited by the short lifetime of ROS, but is also affected by intracellular reducing agents such as glutathione (GSH). The ROS generated during PDT can directly act on the cell membrane, inducing LPO and thereby achieving efficient tumor suppression (Deng et al., 2022). ROS can directly act on the cell membrane, effectively increasing membrane permeability, disrupting membrane integrity, and leading to the rapid release of intracellular contents, thereby inducing necroptosis cancer theranostics (Niu et al., 2022) and ICD (Tang et al., 2023).

Lysosomes are crucial for maintaining normal cellular turnover, and have been implicated in various diseases, including cancer (Zhu et al., 2020). The integrity of the lysosomal membrane is essential for its physiological functions (Cao et al., 2021). However, studies have shown that the permeability of the lysosomal membrane can be influenced by ROS, thereby inducing a cathepsin-mediated lysosomal cell death pathway, which operates distinctly from apoptosis mediated by caspases (Figure 2A) (Wu et al., 2022; Liu X. et al., 2023). Consequently, employing photosensitizers to generate ROS with the aim of altering the integrity and functionality of lysosomal membranes may emerge as a promising therapeutic strategy for cancer treatment (Chen Z. et al., 2025). In recent years, growing evidence has confirmed that lysosomes play a critical role in the activation of pyroptosis (Zheng Z. et al., 2021; Luo et al., 2024). Specifically, when lysosomes are damaged, they release cathepsin B, which subsequently activates the NLRP3 inflammasome and caspase-1, ultimately leading to pyroptotic cell death mediated by GSDMD-N (Liu et al., 2024c; Sun et al., 2024). Moreover, recent studies have indicated that alterations in lysosomal membrane permeability can impair the ability of lysosomes to maintain cellular homeostasis, ultimately leading to lysosome-mediated cell death mechanisms (Li et al., 2023; Xie Z. et al., 2023).

The Mitochondria could generate ATP through oxidative phosphorylation and play a central role in apoptosis regulation (Kilbride and Prehn, 2013; Yadav et al., 2015; Kuznetsov et al., 2022; Khaliulin et al., 2025). ROS generated during PDT can effectively disrupt the mitochondrial membrane potential, leading to mitochondrial dysfunction (Yang F. et al., 2023). This helps prevent further O₂ consumption by mitochondria, thereby enhancing the efficiency of O₂-dependent PDT in producing more ROS (Figure 2B). Moreover, studies have shown that mitochondria are highly enriched with GSH, an important antioxidant molecule (Liu Y. et al., 2023). Therefore, directly targeting mitochondria may offer a more direct way to impair cellular defense mechanisms. Mitochondrial damage is one of the most effective PDT targets due to its direct involvement in programmed cell death (Yan et al., 2024).

The Nucleus can store genetic material (DNA) and controls gene expression and cell proliferation (Sabari et al., 2020; Kalukula et al., 2022). Nuclear damage induced by PDT can lead to DNA fragmentation and irreversible cell cycle arrest (Zhang et al., 2023c). Moreover, studies have shown that photoactive materials targeting the nucleus can generate ROS upon light irradiation, which directly damage nuclear DNA (Figure 2C). The resulting cytosolic DNA fragments can then work in synergy with STING agonists to activate the innate anti-tumor immune response (Wu Y. et al., 2024; Feng et al., 2025).

Photosensitive agents targeting the ER can induce significant ER stress upon light exposure, leading to the surface expression of calreticulin (CRT) (Figure 2D) (Li et al., 2019). This process stimulates the antigen-presenting capability of dendritic cells and triggers ICD, thereby suppressing cancer cell proliferation. A number of studies have demonstrated that both ER stress and ROS production play critical roles in activating intracellular signaling pathways that regulate ICD (Deng H. et al., 2020). PDT with ER-targeting specificity can further enhance the antitumor therapeutic effect.

Research indicates that the Golgi apparatus serves as a key site for the production of various immunosuppressive cytokines. The generation of these cytokines relies on the structural integrity of the Golgi, making it an effective strategy to suppress their expression by disrupting this organelle. Therefore, PDT-induced ROS can impair Golgi function and thereby prevent the release of immunosuppressive factors, which would otherwise hinder the immune response triggered by PDT (Chen Y. J. et al., 2023). This approach enhances the overall efficacy of PDT in inhibiting cancer cell proliferation. Moreover, Golgi-targeted photosensitizers can upregulate the expression of NLRP3 upon light activation, promoting the release of pro-inflammatory cytokines such as IL-1β (Hu et al., 2023). This not only strengthens innate immunity but also boosts adaptive immune responses against tumor cells. Hence, a precise phototherapy strategy targeting the Golgi apparatus offers a promising new direction for effective tumor suppression (Shi et al., 2024).

By selectively delivering photosensitizers to specific subcellular organelles, PDT can be optimized to induce site-specific damage, thereby enhancing therapeutic efficacy and addressing key challenges such as hypoxia, drug resistance, immune suppression, and tumor recurrence (Wang et al., 2021; Tian et al., 2024). A deeper understanding of the unique biological functions and characteristics of each organelle lays the groundwork for developing more effective and precisely targeted PDT strategies.

Cancer treatment remains one of the key research areas in the field of biomedicine (Shen et al., 2024; Wu D. et al., 2024; Ye et al., 2024; Yu et al., 2024b). The continuous development of effective and safe nanodrug delivery systems is not only crucial for advancing cancer therapy but also an urgent and ongoing research priority. Indeed, mitochondria play a pivotal role in cancer cellular energetics (Ikeda et al., 2021). Often referred to as the “powerhouses” of eukaryotic cells, these organelles are responsible for producing the majority of ATP, the cell’s universal energy currency (Wang H. et al., 2024). This process occurs through oxidative phosphorylation, a series of reactions that take place in the inner mitochondrial membrane (Vercellino and Sazanov, 2022; Decker and Funai, 2024). Developing mitochondria-targeted nanomedicine systems can enhance the therapeutic effects of PDT by leveraging the cascade of mechanisms triggered by mitochondrial dysfunction (Ding et al., 2025). A comprehensive overview of diverse mitochondria-targeted PDT strategies, spanning GSH depletion, O₂ generation, mitochondria respiration inhibition, and O₂-independent radical production, are systematically summarized in Table 2.

Lysosomes are organelles that contain large amounts of cathepsin to perform key cellular catabolic processes, which are essential for maintaining cell homeostasis and regulating various cellular processes (Zhang Z. et al., 2021; Gros and Muller, 2023). Different from the normal cells, lysosomes in tumor cells are more plentiful with altered morphology, which upregulated lysosomal activity in tumor tissue is related to the metabolic need of fast proliferating tumors (He et al., 2023; Jia et al., 2023). In tumor tissue, photosensitizers localized in the lysosome may cause selective damage to lysosomes and induce subsequent cathepsin release into the cytoplasm, trigger cell death, and finally postpone the progression and metastasis of tumors.

The alteration of lysosomal membrane permeabilization (LMP) can disrupt the function of lysosomes and even cause lysosome-dependent cell death (Tanaka et al., 2022). By inhibiting the leakage of photosensitizers from lysosomes, constant LMP and unrecoverable damage to cancer cells could be motived under light irradiation, thus the efficiency of PDT substantially improved. Encourage by this, Li et al. reported lysosome-targeting nanophotosensitizer (BDQ-NP) based on boron-dipyrromethene (BOD) derivatives with an amphiphilic structure (synthesized via a reaction involving BOD core modification and hydrophobic chain conjugation) for highly effective PDT (Figure 8A) (Li et al., 2023). Amphiphilic BDQ could be synthesized in four steps by BOD and subsequently self-assembled into nano-sized particles (BDQ-NP) in aqueous solution at a concentration of 0.5 mg/mL under mild stirring (200 rpm) for 2 h. Owing to the pH-dependent lysosome-targeting property (facilitated by protonation of amino groups in the acidic lysosomal environment), BDQ powerfully incorporates into the lipid bilayers of lysosomes and induces continuous LMP through ROS-mediated LPO. Under light irradiation (660 nm, 10 mW/cm²), BDQ-NP produced a substantial amount of ROS, and disrupted functions of lysosome and mitochondria via activating the cathepsin B-mediated mitochondrial damage pathway. Specifically, cathepsin B cleaves pro-apoptotic proteins to trigger outer membrane permeabilization, releasing cytochrome c and initiating caspase-dependent apoptosis. After intravenous injection, BDQ-NP achieved high accumulation in tumors as well as a fantastic PDT effect on subcutaneous colorectal CT26 tumors and orthotopic 4T1 breast carcinomas with low systemic toxicity. In addition, PDT mediated by BDQ-NP also efficiently hindered lung metastasis of 4T1 breast carcinomas by reducing MMP-9 expression (downregulated by 42%) via lysosomal damage. This work highlights the potential value of self-assembled lysosome-targeted photosensitizers for augmented PDT effect against tumor metastasis.

The characteristics of inherent chirality, nonplanarity, and structural controllability make helicenes promising candidates in the field of optoelectronics and biomedical applications (Bouz et al., 2025). Nevertheless, the poor water solubility of helicenes strictly restricts their biological applications for organelle-targeted type I and II PDT (Yang et al., 2024). To overcome these limitations, water-soluble nanoparticles named D7H-NPs comprising twisted double [7]carbohelicene (D7H) were fabricated for lysosome-targeted bioimaging and advanced PDT (Zhao et al., 2022). As shown in Figure 8B, D7H was reprecipitated with amphiphilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000) to prepare self-assembled D7H-NPs via the nanoprecipitation method (Zhao et al., 2022). The resulting D7H-NPs displayed a uniform size of 46 ± 2 nm and exhibited superior water solubility. Especially, D7H-NPs could specifically gather in the lysosomes of 4T1 tumor cells, suggesting their ability of lysosome-targeted bioimaging. Moreover, the extensive production of •O₂ ⁻ and ¹O₂ derived from D7H-NPs was noticed upon light excitation, thereby triggering tumor cell apoptosis. This work contributes a promising phototherapeutic agent based on helicenes concerning type I/II PDT, manifesting a facile strategy for organelle-targeted enhanced PDT therapy.

On account of light-triggered lysosomal disruption is beneficial for tumor therapy, a photo-activable theranostic nanoplatform (TPIMBS NPs) based on a synthetic multifunctional molecule (TPIMBS, chemical structure containing a cyanine dye core, organosilver moiety, and PEGylated segment) was constructed for spatiotemporally-controllable synergistic tumor therapy (Figure 8C) (Liu X. et al., 2023). With rational design, the synthetic TPIMBS photosensitizer exhibited function of aggregation-induced NIR emission and utilized organosilver as a chemotherapeutic agent. The amphiphilic block copolymers (DSPE-PEG-2000) at a mass ratio of 1:3 (TPIMBS:polymer) was introduced to assisted TPIMBS self-assemble into nanoparticles, rendering TPIMBS NPs a prolonged blood circulation half-life time of 12.5 h as well as expanded tumor accumulation via passive targeting. Through photochemical internalization, TPIMBS NPs favorably focused on the lysosomes of tumor cells and created ROS under light irradiation, leading to lysosomal disruption and release of Ag⁺ and cathepsin B from TPIMBS NPs. Cathepsin B contributes to both mitochondrial damage and inflammasome activation via the NLRP3 inflammasome/caspase-1/GSDMD-N pathway. Moreover, the release Ag⁺ could serve as a chemotherapeutic agent, which inhibits thioredoxin reductase and DNA polymerase to block multiple enzymatic pathways and result in cell apoptosis, significantly boosting the systemic antitumor efficacy by synergism with PDT (tumor inhibition rate = 91% vs. 65% for monotherapy). Notably, TPIMBS NPs with excellent stability can persevere accumulation at the tumor site for up to 36 h for prolonged bioimaging, and possess the desirable capability for tumor elimination in in vivo experiments. This nanoplatform exploits the combination of lysosomal-targeted ROS production with the photoactivable release of chemotherapeutic Ag⁺, to realize a spatiotemporally-controllable antitumor effect.

Accumulating evidence demonstrates that regular lysosomal function plays a critical role in autophagic degradation and the activation of pyroptosis (Liu Y. et al., 2024; Zhu et al., 2025). Inspired by the function of lysosome closely related to pyroptosis and autophagy, Sun et al. rationally synthesized a boron-dipyrromethene dimer (BDPd) comprising two lysosomal-targeted morpholine groups as NIR photosensitizer to augment PDT/PTT (Figure 8D) (Sun et al., 2024). To facilitate internalization into cancer cells, the synthesized BDPd was further self-assembled together with amphiphilic triblock copolymer (Pluronic F127) to prepare nanosized micelles (named BDPd NPs). BDPd NPs exhibited good biocompatibility, high ROS production yield, and excellent photothermal abilities. The perfect lysosomal-targeting capability endows BDPd NPs accumulating in lysosomes and stimulates vigorous lysosomal damage by boosted ROS under NIR laser irradiation, thus increasing the killing efficiency of 4T1 cancer cells. Mechanistically, BDPd NPs could efficiently damage the lysosomal and mitochondrial of cancer cells, activate ICD marker exposure, and trigger pyroptosis through simultaneously stimulating caspase-3/GSDME and NLRP3/GSDMD pathway, subsequently promoting DCs maturation. More importantly, the destruction of lysosomal functions in-turn blocks self-protective autophagic degradation, thus losing cytoprotection towards cancer cells. Either intratumoral or intravenous injection, BDPd NPs substantially suppressed tumor growth upon NIR light activation, provoked robust antitumor immune responses, and prevented tumor recurrence in breast tumor-bearing mouse models. Collectively, this work highlights the close relationship between subcellular organelles and PTT/PDT with advanced nanotechnology, to amplify the therapeutic outcomes in the future.

Metabolism imbalance advances the tumor aggressiveness and resistance towards therapies, therefore cell nucleus regulating cellular metabolism and heredity becomes a brightening subcellular therapeutic location (Pham et al., 2023). Nucleus-targeted photosensitizers can apply pressure to DNA replication, facilitate apoptosis of cancer cells, as well as provoke inflammatory cells via secreting extensively proinflammatory factors and stimulate antitumor immune response (Liu et al., 2021). Targeting the DNA damage response and DNA repair capacity in cancer cells has been recognized as an important anti-cancer strategy in recent years (Chen M. et al., 2023). Accordingly, manners to target the nucleus of tumor cells are considered a perfect target for opening the complete potential of tumor phototherapy (Wang P. et al., 2024). However, nucleus-targeting drugs with high efficiency and biosafety characteristic are recently rare.

Encouraged by nucleus-targeting photosensitizers-mediated PDT can elicit innate immune response for long-term immunotherapy, the combination of aPD-L1 with photoimmunotherapy is promising for reversing the immunosuppressive microenvironment and minimizing tumor recurrence (Zhang et al., 2023c). Zhang et al. constructed a novel nanomaterial named as PZGE by employing graphene quantum dots (GQDs) to loaded PD-L1 molecular antibody (aPD-L1) and zinc phthalocyanine (ZnPc) to promote innate immune response and transpose immunosuppressive microenvironment (Figure 9A) (Zhang et al., 2023c). To investigate the relationship between nucleus entry capacity and nanoparticle size, PZGE with three different particle sizes (5 nm, 32 nm, 200 nm) were synthesized. Then, the CCK-8 assay was employed to quantify their phototoxicity (Xiong et al., 2020; Cheng et al., 2021; Hu et al., 2021). Notably, PZGE with particle size of 5 nm exhibited the best nucleus enrichment ability due to its ultrasmall size, and amplified DNA destruction by nucleus-located PDT. Antitumor immunity was activated via cGAS/STING/IFN I pathway, followed by cytotoxic T lymphocyte infiltration and PD-L1 expression reversion. Besides, PZGE upon light irradiation effective inhibited the oral squamous cell carcinoma in vivo. Immunotherapy has introduced innovative design concepts and broad application prospects for the treatment of malignant tumors (Ge et al., 2023; Huang et al., 2023). The combination of phototherapy and immunotherapy offers a promising new approach in the fight against cancer (Liang et al., 2023). This work displays a size-dependent strategy of nucleus-targeted PDT and provides new insight into nucleus-targeting photo-mediated immunotherapy for “immune cold” tumors.

The combination of PDT and STING agonists has been shown to strongly augment the efficacy of antitumor therapy, so local delivery of photosensitizers and STING agonists based on nanoplatforms is expected to maximize tumor elimination (Ding et al., 2024). A nucleus-targeted chimeric peptide nanorod referred PFPD was constructed for antitumor precision therapy, which could enhance innate immunity through PDT-mediated local DNA damage and STING activation. Utilizing intermolecular forces, a photosensitizer (protoporphyrin IX, PpIX) was coupled onto multifunctional FFVLKPKKKRKV peptide and a novel chimeric peptide (PpIX-FFVLK-PKKKPRV) produced, which was self-assembled to form nanorods and loaded with DMXAA (a STING agonist) (Figure 9B) (Wu Y. et al., 2024). PFPD has a uniform and small size distribution with good stability, rendering its intratumor accumulation, cell internalization, and nucleus-targeted delivery of payloads. When exposure to laser, large amounts of ¹O₂ produced by PFPD induces in situ DNA fragmentation in nucleus, while the released cytoplasmic DNA fragments subsequently combined with the STING agonist to stimulate innate antitumor immunity. In addition, PFPD triggered ICD effect through nucleus-localized PDT, activated natural killer cells (NKs) and T cells, thus effectively eradicating primary and metastatic tumors with ignorable side effects. This research offers valuables for precise drug delivery and combination therapy against metastatic tumors with poor prognosis.

To deliver drugs to the nucleus of tumor cells more accurately, a hierarchical targeting cascade system towards tumor cells and the nucleus has been developed for tumor eradication through self-enhancement of PDT and chemotherapy. Specifically, a nucleus-targeting nanoprodrugs named HPC-CAT/CL were prepared based on human serum albumin (HSA), Ce6, a cisplatin prodrug (Pt (IV)), catalase (CAT), and b-cyclodextrin-lysine (CL) (Yang et al., 2023c). Then, the surface functionalization of HPC-CAT/CL was performed by a targeting agent (AS1411 aptamer), and the resulting HPC-CAT/CL-AP could actively target tumors, thus achieving self-reinforcing cascade photochemotherapy. HPC-CAT/CL-AP were efficiently taken up by tumor cells and accumulated in the nucleus, and non-toxic Pt (IV) prodrug was effectively reduced to its active state Pt (II) and supplied H₂O₂ simultaneously when exposed to overexpressed GSH in tumor cells and nucleus. Noteworthy, H₂O₂ could be decomposed by CAT to produce O₂, which effectively alleviated the influence of anaerobic environment on the curative effect of PDT, and accordingly realized the synergistic photochemotherapy effect. The in vitro and in vivo experiments showed that HPC-CAT/CL-AP was highly successful to kill tumor cells, significantly repressing tumor growth and lung metastasis. This nucleus-targeted self-augmenting cascade photochemotherapy strategy has enormous potential in overcoming recurrence and metastasis of tumors.

Beyond traditional nucleus-targeting strategies (e.g., size control, peptide-mediated delivery, and oligonucleotide aptamers targeting nuclear proteins), recent advances in s in nucleus-targeted PDT have focused on specific recognition of nuclear nucleic acids, including G-quadruplexes (G4s) and general RNA/DNA, to enhance targeting precision and therapeutic efficacy (Long et al., 2024; Chen W. et al., 2025).​ G4s are stable secondary structures formed by guanine-rich nucleic acids in oncogene promoters and telomeres, making them attractive targets for selective tumor intervention (Liu et al., 2024a). Building on this foundation, an advanced donor-π-acceptor (D-π-A) acridinium-based Type I photosensitizer was developed for RNA G4s targeting (Chen W. et al., 2023). Its structure integrates triphenylamine (electron donor) and pyridinium (electron acceptor) to achieve NIR absorption and efficient electron transfer. This acridinium derivative specifically recognizes RNA G4s through hydrogen bonding, with negligible affinity for double-stranded DNA or single-stranded RNA. Upon light irradiation, it predominantly generates •O₂ ⁻, instead of ¹O₂, overcoming hypoxia-induced PDT resistance and enhancing ICD in tumors.

Additionally, direct targeting of nuclear RNA/DNA via sequence complementarity or intercalation has also advanced PDT precision. A nucleus-targeted activatable photosensitive probe (CMT-I) was designed and synthesized for DNA targeting (Liao et al., 2025). Molecular docking analyses indicate that CMT-I binds to DNA selectively, relying on hydrogen bonds and π-π conjugation for interaction. In vitro spectral tests show that ct-DNA specifically activates CMT-I, leading to a notable fluorescence enhancement upon binding. When irradiated with light, CMT-I proves effective at generating ¹O₂ RNA sequencing studies reveal that the PDT induced by CMT-I activates tumor cell immunity, initiating an adaptive immune response. In vivo therapeutic trials further confirm that CMT-I boosts antitumor immunity, a key factor in successfully eliminating immunologically cold tumors, and underscores the value of nucleus-targeted PDT for precise cancer treatment. Together, these G4-and nucleic acid-targeted approaches represent a paradigm shift from broad nuclear localization to molecularly precise damage, with successive advancements significantly improving PDT efficacy and reducing systemic toxicity.​

Due to ROS possess a short half-life and a restricted effective diffusion radius, the introduction of photosensitizers to produce ROS in situ on target organelles is essential to avoid their rapid decay. Among these, the plentiful unsaturated lipids of the plasma membrane can stimulate LPO under the action of ROS produced by PDT, thus damaging the cell integrity (Fan et al., 2021). Therefore, photosensitizer-based cell membrane-targeted delivery systems can improve membrane permeability, cause LPO, disrupt membrane integrity, and ultimately result in cell membrane disruption and release of cell payloads (Wang M. et al., 2022). In recent years, membrane-targeted photosensitizer systems have been established, which could deliver photosensitizers to therapeutic target organelles to enhance the efficiency of PDT (Yang et al., 2023b).

To amerliorate phototherapy-mediated tumor metastasis suppression, self-delivery chimeric peptide (C₁₆-CypateRRKK-PEG₈-COOH, CCP) was designed for cell membrane-targeted low-temperature PTT and PDT combination therapy. As depicted in Figure 10A, CCP was constructed from palmtic acid-modified NIR dye (Cypate, hydrophobic) and chimeric peptide Arg-Arg-Lys-Lys-PEG₈ (RRKK-PEG₈-COOH, hydrophilic), whose amphiphilicity gives it the ability to self-assemble into nanoparticles (CCP NPs) (Chen et al., 2022). Among them, Cypate is a photosensitive agent for clinical use with dual effects of PDT and PTT (Zou et al., 2025b), positively charged RRKK fragment and alkyl chain of palmitic acid enable CPPs to target and insert into the cell membrane, and PEG chain endows prolong the blood circulation time of CCP NPs. CCP NPs exhibited strong tumor targeting and accumulation capability, which could effectively kill tumor cells. Under NIR laser irradiation, CCP NPs can produce numerous ROS and mild heat of less than 45 °C locally in the cell membrane, destroy the cancer cell membrane, effectively induce ICD, and activate antitumor immune response, thereby eliminating residual tumor cells. Under single administration and NIR light irradiation, CCP NPs significantly inhibited tumor growth and lung metastasis, thus extending the survival time of mice. This unique cell membrane-targeted phototherapy strategy helps to achieve tumor clearance and inhibit metastasis in a safe and effective manner.

As a form of programmed cell death caused by inflammasome, pyroptosis is an important means to overcome drug resistance towards apoptosis and fight against immunosuppressive tumor microenvironment, and ultimately inhibit tumor growth (Loveless et al., 2021; Zhu Y. et al., 2024). However, the current pyroptosis-induced drugs have some limitations, such as high toxicity, poor stability, and low intracellular accumulation. In view of this, a cell membrane-targeting photosensitizer dimer (D1) with aggregation-induced emission properties was constructed for synergistic pyroptosis-mediated photodynamic and photothermal immunotherapy. In detail, a π-conjugated chromophore with strong intramolecular charge transfer ability was formed by thiophene, triphenylamine, and pyridinium groups, and then linked two chromophores with one flexible octyl group to construct the dimeric photosensitizer D1 (Figure 10B) (Tang et al., 2023). This photosensitive dimer D1 could specially accumulate on the cell membrane, and generate ROS by type I PDT as well as heat energy by PTT under light irradiation, enabling a reinforced pyroptosis effect. Additionally, the pyroptosis triggered by synergistic phototherapy effectively triggered the discharge of inflammatory cytokines and intracellular contents, promoted tumor-specific antigen induction and DCs maturation, and stimulated T cell proliferation, thus activating systemic antitumor immunity. In mechanism, D1 exhibits improved permeability and retention effect in the tumor cell membrane, high ROS-generated efficiency, and strong photothermal effect, which accelerates pyroptosis-mediated synergistic PDT/PTT/immunotherapy in mouse models. After 7 days of treatment with laser irradiation, D1 was found to completely eliminate the primary tumors and effectively inhibit the distant tumors. This work provides a promising strategy for a satisfactory antitumor effect and rouses systemic immune response against tumor metastasis.

By self-assembly of chemotherapeutic agent sorafenib and plasma membrane-targeted amphiphilic chimeric peptide (Pal-K(PpIX)-R₄), Deng et al. have successfully prepared a nanoscale photooxidant named as SCPP (Figure 10C) (Deng et al., 2022). Among them, the palmitic part and positively charged peptide of Pal-K(PpIX)-R₄ (hydrophobic) given the SCPP plasma membrane-targeting capability. SCPP displayed excellent stability and ideal size distribution, which could enhance localized LPO production by in situ PDT with laser. In addition, intracellular accumulation of the chemotherapy drug (sorafenib) can downregulate the levels of GSH and glutathione peroxidase 4 (GPX4) by blocking the expression of cystine/glutamate antiporter (SLC7A11), thereby amplifying the PDT effect and disrupting the antioxidant defense system. Therefore, SCPP could trigger LPO through plasma membrane-targeting PDT, and activate ferroptosis of tumor cells through sorafenib-mediated chemotherapy, finally exhibiting superior tumor inhibition ability in vivo. This work may afford scientific direction for plasma membrane-targeted synergistic treatment of tumors when exposure to disadvantage conditions.

Ribosomes are highly complex cellular machines, primarily composed of ribosomal RNA (rRNA) and dozens of different ribosomal proteins (R-proteins); the exact number varies slightly between species (Cheng et al., 2024). These ribosomal proteins and rRNA are arranged into two subunits of different sizes, commonly referred to as the small and large subunits of the ribosome (Elhamamsy et al., 2022). These subunits work together to convert mRNA into polypeptide chains during protein synthesis (Jiao et al., 2023). It has been reported that cancer stem cells (CSCs) have a higher abundance of ribosomes than those found in normal cells, which is one of the important markers of CSCs (Xue et al., 2024). The proportion of ribosomes in the body determines the total proteome and the rate of cell division, thus influencing the cell cycle and its fate. Due to the negative charges of ribosomes, positively charged materials interact strongly with ribosomes to achieve targeting. Qin’s group (Figure 11) first synthesized a positively charged photosensitizer (meso-Tetra (4-aminophenyl)Porphyrin, m-TAPP) and small peptides (N-fluorenylmethoxycarbonyl-leucine-leucine-leucine-OMe, Fmoc-L3-OMe) that co-assemble into nanoparticles based on π-π interactions (Wang J. et al., 2022). The pH of tumor cells is 6.5 lower than that of normal cells, which allows the positively charged co-assembly to interact strongly with ribosomes for effective targeting. The co-assembly exhibits strong ROS production under light irradiation, significantly reducing tumor stem cells and deactivating ribosomes, and inhibiting tumor cell growth both in vitro and in vivo.

The ER is a multifunctional organelle responsible for maintaining cell homeostasis, protein synthesis, folding, and secretion. The production of ROS by PDT could disrupt the protein-folding capacity of this organelle and trigger ER stress, which leads to tumor cell death (Diao et al., 2025). Therefore, targeting the ER is critical to evoke ER stress.

The Golgi apparatus (GA) functions as a vital organelle in the intracellular membrane transport network, acting as a crossroads for extracellular and intracellular pathways (Xu et al., 2024). It is fundamental in the processing, sorting, and trafficking of proteins synthesized within the cell, ensuring their proper delivery to the intended destinations. The generation of ROS can adversely affect the structure and function of the GA, potentially leading to modifications in stress signaling pathways downstream (Hu et al., 2023). Such alterations may play a role in inhibiting tumor cell growth, contributing to the activation of cellular stress responses such as apoptosis or cell cycle arrest.

Autophagy is a highly conserved lysosomal-mediated degradation process in eukaryotes. Autophagosomes, which are double-membrane vesicles formed during autophagy, encapsulate autophagy substrates and transport them to lysosomes for degradation (Liu et al., 2024b). This process is crucial for cell survival, growth, and homeostasis. Reports indicate that PDT efficacy is enhanced in tumor cells when autophagy is suppressed by inhibitors. Zhang et al. developed an adenosine-triphosphate (ATP)-regulated ion transport nanosystem, comprising a porphyrinic porous coordination network (PCN) and squaramide (SQU) (Figure 15A) (Wan et al., 2019). The release of SQU in response to high ATP levels inhibits autophagy by disrupting cellular ion homeostasis, sensitizing PDT, and improving its therapeutic efficacy. Conversely, Jin’s group studied acid-sensitive CD-Ce6-3BP nanoparticles loaded with the respiration inhibitor 3-bromopyruvate (3BP) and the photosensitizer Ce6, facilitated by host-guest interaction (Figure 15B) (Deng Y. et al., 2020). 3BP reduces intracellular O₂ consumption, alleviating tumor hypoxia, and converting autophagy from a pro-survival to a pro-death process. This excessive activation of autophagy enhances the PDT effect.

In recent years, PDT has emerged as a minimally invasive, highly regulable, and immunogenic therapeutic strategy that holds great promise in the field of cancer treatment. Despite its growing popularity and notable achievements in preclinical studies, several critical challenges remain before PDT can be widely adopted in clinical practice-particularly in improving therapeutic efficiency, enhancing targeting specificity, and overcoming tumor microenvironmental limitations. This review systematically summarizes recent advances in subcellular organelle-targeted PDT strategies aimed at enhancing therapeutic outcomes. Particular emphasis is placed on nanoplatforms designed to target mitochondria, lysosomes, the nucleus, cell membrane, Golgi apparatus, and ribosomes, with detailed discussion of their targeting mechanisms and underlying pathways that contribute to enhanced PDT efficacy. These approaches not only improve the accumulation of photosensitizers at specific organelles but also modulate key intracellular signaling and oxidative stress responses, thereby potentiating antitumor effects.

Although numerous studies have demonstrated the therapeutic potential of PDT, several key issues still need to be addressed. First, in terms of drug delivery, many currently used photosensitizers suffer from poor water solubility and limited stability in vivo, often requiring complex delivery systems for effective administration. This increases formulation complexity and may compromise bioavailability. Secondly, most photosensitizers inherently lack targeting ability and must be conjugated-either covalently or non-covalently-to targeting ligands such as peptides, antibodies, or small molecules to achieve precise subcellular localization. Such multi-step functionalization processes further complicate preparation and may lead to batch-to-batch variability. Moreover, the hypoxic tumor microenvironment remains a major obstacle to efficient ROS generation during PDT. While various strategies-such as O₂-carrying materials, catalytic H₂O₂ decomposition, or mitochondrial respiration inhibition and regulation-have shown promising results in cellular and animal models, their safety and efficacy in humans remain to be fully validated. Additionally, most conventional photosensitizers rely on visible light excitation, which limits tissue penetration and restricts their application to superficial tumors. Therefore, developing photosensitizing systems responsive to NIR or X-ray irradiation could significantly expand the clinical applicability of PDT. Finally, the high interstitial pressure and dense extracellular matrix within solid tumors pose significant barriers to effective drug delivery. As a result, the concentration of systemically administered nanomedicines reaching the tumor site is often insufficient. To address this challenge, biomimetic delivery systems-such as cell membrane-coated nanoparticles or exosome-based carriers-along with active targeting strategies may offer promising solutions to enhance tumor accumulation and therapeutic performance.

From the clinical translation perspective, subcellular organelle-targeted PDT faces multiple bottlenecks hindering its transition from lab to clinic. Insufficient pharmacokinetic data on nano-photosensitizers impedes precise control of dosage and frequency, raising clinical risks. The lack of long-term biosafety assessments is a major concern, as some nanomaterials may accumulate in vivo, causing chronic toxicity or immune reactions that require long-term monitoring. Additionally, standardizing light irradiation doses in multi-center trials is challenging, in which variations in equipment, duration, and intensity reduce result comparability, hampering unified clinical standards.​ Notably, clinical experience with second-generation photosensitizers such as ALA in treating condyloma acuminatum, encompassing administration protocols, irradiation parameters, and efficacy assessment, provides a valuable reference for the design of subcellular PDT. The steps for promoting clinical translation involve strict screening of biocompatible, stable nanocarriers (material level), comprehensive evaluation of tumor targeting/killing (cellular level), in-depth in vivo pharmacokinetic and toxicity studies (animal level), and well-designed multi-center trials (clinical level). Collaborating with regulators to develop tailored approval standards will accelerate translation of photosensitizers to clinical use.

In terms of emerging trends, interdisciplinary integration drives PDT development. Deep integration with artificial intelligence enables accurate prediction of patient responses to PDT by building tumor models and analyzing clinical data, optimizing light parameters for personalized treatment based on tumor heterogeneity. Combining with immune checkpoint inhibitors creates synergy: PDT releases tumor-associated antigens to activate immunity, while inhibitors enhance the immune system’s ability to recognize and eliminate tumor cells, strengthening systemic anti-tumor immunity. Technically, activatable photosensitizers remain inert in normal physiology but activate to generate ROS upon sensing tumor microenvironment signals (e.g., low pH, high ATP, specific enzymes), achieving precise tumor killing. Multimodal platforms integrate imaging, PDT, and PTT, with real-time imaging monitoring tumor location, size, and treatment changes to guide therapies and improve efficacy. Additionally, PDT’s applications extend beyond tumors, encompassing effective killing of bacteria, fungi, and viruses (especially drug-resistant strains) without inducing resistance, as well as clearing abnormally aggregated proteins and reducing neuroinflammation in neurodegenerative diseases.

In conclusion, by deeply exploring subcellular targeting mechanisms and combining advanced materials science with biological insights, the performance of PDT is expected to be further optimized. Especially under the premise of overcoming the above challenges, accelerating clinical translation, and keeping up with emerging trends, subcellular organelle-targeted PDT is expected to break through the limitations of existing clinical treatments in the future, achieve breakthrough expansion of clinical indications, gradually expand from the current treatment of some cancers to more disease fields, transition to a wider range of clinical applications, and make greater contributions to the cause of human health.