Aug 2026· Small· pp.
e75270
· 0 citations· 29 references
Medicine
TL;DR
This work provides an oxygen-unrestricted synergistic strategy to compensate for the limitations of standalone Type II PSs or HAPs monotherapy, offering valuable insights for clinical cancer treatment.
Abstract
The oxygen heterogeneity within tumors restricts the therapeutic efficacy of hypoxia-activated prodrugs (HAPs) and traditional photosensitizers (PSs) when administered alone. To overcome this limitation, we present an oxygen-unrestricted synergistic therapeutic strategy to concurrently potentiate treatment efficacy in both hypoxic and normoxic tumor compartments. By introducing TEMPO, we developed an efficient PS capable of simultaneous Type I and Type II photocatalytic reactions. This PS, named DT, was co-encapsulated with the HAP TH-302 into a tumor-targeting nanoparticle system, DT@TH302, which exhibits mitochondrial localization. Upon photoactivation, DT@TH302 generates substantial amounts of singlet oxygen and superoxide anion, while disrupting the cellular NAD+/NADH redox equilibrium, leading to catastrophic mitochondrial dysfunction. The oxygen consumption during photodynamic therapy (PDT) further aggravates local hypoxia, thereby activating TH-302 to induce DNA cross-linking and promote tumor cell apoptosis. Meanwhile, DT-mediated PDT remains effective through a hypoxia-tolerant Type I mechanism. Moreover, the treatment triggers immunogenic cell death, demonstrating considerable potential for immunotherapy. In vivo, DT@TH302 exhibits excellent biosafety and tumor-targeting capability, resulting in significant tumor growth suppression. This work provides an oxygen-unrestricted synergistic strategy to compensate for the limitations of standalone Type II PSs or HAPs monotherapy, offering valuable insights for clinical cancer treatment.
This review constructs a refined mechanistic framework to elaborate the complementary mechanisms of PDT and PTT toward CDT in terms of reaction kinetics modulation, endogenous substrate replenishment, and tumor antioxidant defense inhibition, and the key bottlenecks hindering clinical translation.
Yuxuan Ma, Jie Gong, Zixuan Wu et al.· International Journal of Nan...· 0 citations
Photodynamic therapy (PDT) faces severe clinical limitations due to tumor hypoxia and an immunosuppressive microenvironment. To address these challenges, we rationally designed a rhenium-based system, RGCS@PEG nanoparticles. This platform incorporates a Cu-doped mesoporous silica core as an efficient carrier for the simultaneous loading of a rationally engineered Re-Bodipy photosensitizer (Re3) and the nitric oxide (NO) donor S-nitrosoglutathione (GSNO). The entire assembly is further coated with reactive oxygen species (ROS)-responsive thioketal-linked polyethylene glycol, enabling targeted payload release in the tumor microenvironment. The molecular design of Re3 facilitates highly efficient superoxide radical (˙O2−) generation via a nicotinamide adenine dinucleotide (NADH)-oxidation-driven photocatalytic cycle, initiating oxygen-independent type-I PDT. Concurrently, the GSNO-derived NO not only exerts direct cytotoxicity but also reacts with ˙O2− to form highly toxic peroxynitrite (ONOO−), thereby triggering a self-amplifying reactive nitrogen species (RNS) storm even under hypoxia. This cascade effectively eradicates hypoxic tumors by inducing ferroptosis-dominated immunogenic cell death. Furthermore, the RNS storm directly downregulates the immune checkpoint protein CD24, alleviating immunosuppression. Collectively, this RNS-amplifying nanoplatform represents a strategy that moves beyond conventional PDT by synergistically integrating gas therapy and checkpoint downregulation to remodel the tumor microenvironment and amplify antitumor immunity.
Long-Bo Yu, Qing-Hua Shen, Shuo-Ting Huang et al.· Chemical Science· 0 citations
Photodynamic therapy (PDT) efficacy is severely compromised by tumor hypoxia and the scarcity of efficient type-I photosensitizers, necessitating multimodal therapeutic strategies. Herein, we report a porphyrin-Cu (II) covalent organic framework (TBCOF) with intrinsic bifunctional photodynamic and chemodynamic activities. Sequential DOX encapsulation and hyaluronic acid (HA) surface functionalization afford HA-TBCOF@DOX, a tumor-targeted nanoplatform integrating four synergistic therapeutic modalities. Under 660 nm laser irradiation, the nanoplatform generates ROS signatures consistent with both type-I and type-II pathways for PDT, while the intrinsic Cu2+ centers are proposed to catalyze a Fenton-like reaction consistent with •OH generation for CDT. Concurrently, observations of O2 evolution suggest catalase-like activity that may decompose endogenous H2O2 into O2, alleviating hypoxia and potentiating oxygen-dependent PDT. Efficient photothermal conversion and pH-triggered DOX release contribute to photothermal and chemotherapeutic effects, respectively, while HA-mediated CD44 targeting enhances cellular uptake and therapeutic specificity. In vitro and in vivo studies demonstrate that laser-activated HA-TBCOF@DOX effectively suppresses tumor growth, induces apoptosis, and exhibits no apparent systemic toxicity under the tested experimental conditions. This work establishes a multifunctional COF-based nanoplatform that addresses PDT limitations observed in this study by integrating intrinsic PDT and CDT, providing a robust strategy for synergistic multimodal cancer therapy.
Yongjie Mo, Jie Hou, Hong-Li Li et al.· Materials Today Bio· 0 citations
Hypoxia-induced resistance remains a major obstacle in photodynamic therapy (PDT) due to the oxygen dependency of conventional type-II photosensitizers. To tackle this issue, we developed a phenothiazine-based small molecule (PFI) that integrates intrinsic oxygen-carrying perfluoroalkyl chains with type-I photodynamic functionality. The perfluorinated segments enable localized oxygen enrichment to counteract tumor hypoxia, while the phenothiazine core generates reactive oxygen species (ROS) via an oxygen-independent type-I pathway, sustaining phototoxicity even under low-oxygen environments. Both in vitro and in vivo studies confirm that PFI effectively accumulates in tumors, relieves hypoxia, and achieves potent antitumor efficacy with negligible side effects. This single-component design offers a facile and robust platform for hypoxia-tolerant photodynamic cancer therapy.
Ziqi Zou, Meiying Liu, Kun Zhang et al.· RSC Advances· 0 citations
Achieving precise drug delivery to the tumor site can minimize systemic side effects caused by off-target effects. As a therapy that depends on oxygen content, photodynamic therapy (PDT) is significantly constrained by the hypoxic nature of the tumor microenvironment (TME). Compared with the limited efficacy of single PDT, the combination of multiple treatment modalities can achieve synergistic enhancement and superior therapeutic outcomes. Since carbon radical therapy does not rely on oxygen as a reactive substrate, it is mechanistically complementary to oxygen-dependent PDT. In this work, we report a novel strategy for developing a theranostic nanoplatform for long-lasting PDT activated by 1530 nm laser irradiation and glutathione (GSH)-triggered carbon-centered radical synergistic therapy that responds specifically to the TME. This theranostic nanoplatform (UCNPs@WOR:AF@CDC, UWAC) comprises three components: GSH-responsive engineered vesicles (CDC), functionalized metal-organic frameworks (WOR) encapsulating lanthanide upconversion nanoparticles (UCNPs@WOR, UW), and carbon radical prodrugs (ART-Fe, AF). Lanthanide-based upconversion nanoparticles (UCNPs) could upconvert 1530 nm light to 1390 nm for attenuation-minimized second near-infrared (NIR-II) fluorescence imaging and to visible light that serves as the light source for photocatalysis for water oxidation. The 1530 nm light-activated generation of reactive oxygen species (ROS), enhanced by UW-mediated hydrolytic oxygen evolution, works in synergy with the GSH-triggered release of the carbon radical prodrug (AF) to achieve long-lasting therapeutic outcomes. Importantly, it could achieve tumor-specific drug release, triggered by the degradation of the engineered vesicles in response to elevated GSH levels. This work develops a novel theranostic nanoplatform, which could achieve GSH-activated drug delivery, deep-tissue penetration, and a long-lasting therapeutic effect.
Jitong Gong, Yu Liu, Qingkun Yang et al.· ACS Applied Materials and In...· 0 citations
Synergistic photodynamic and photothermal therapy (PDT/PTT) holds immense promise for cancer treatment, yet its efficacy is often compromised by limited photosensitizer performance, glutathione (GSH)-mediated ROS quenching, and tumor-protective autophagy. Herein, we developed a GSH-responsive hydrophilic porphyrin copolymer (PPS) that covalently integrates porphyrin into the polymer backbone, ensuring high loading capacity and minimal carrier-related toxicity. PPS exhibits robust absorption around 800 nm, enabling simultaneous PDT and PTT under a single NIR laser. By incorporating the autophagy inhibitor chloroquine (CQ), the resulting CQ@DPPS nanosystem achieves multi-modal synergy: intracellularly, CQ not only inhibits phototherapy-induced autophagic flux to suppress cell survival but also facilitates the lysosomal escape of photosensitizers, heightening programmed cell death via Bcl-2 inhibition and Caspase-3 activation. Crucially, CQ@DPPS significantly activates NK cell-mediated innate immune surveillance and enhances the secretion of granzyme B (GZMB) in NK cells by downregulating MHC-I expression on the surface of tumor cells. In vivo, CQ@DPPS combined with 808 nm irradiation achieved complete tumor regression in HCT116-bearing mice and significantly attenuated hepatic metastasis. This work provides a potent strategy to overcome phototherapy resistance through the integration of autophagy inhibition, dual-mode phototherapy, and innate immune activation. STATEMENT OF SIGNIFICANCE: Clinical translation of PDT/PTT therapy is hindered by inefficient photosensitizer delivery, GSH-mediated ROS depletion, and cytoprotective autophagy in tumors. Here, we report a GSH-responsive hydrophilic porphyrin copolymer with porphyrin covalently integrated into the polymer backbone, enabling high loading, reduced carrier burden, and effective 808 nm-triggered PDT/PTT. Co-delivery of CQ in the CQ@DPPS nanosystem not only suppresses protective autophagic flux, but also promotes lysosomal escape, mitochondrial apoptosis, and NK cell-mediated antitumor immunity through reduced MHC-I expression and increased GZMB secretion. This multi-mechanistic platform achieved complete tumor regression and reduced hepatic metastasis in vivo, offering a promising biomaterial strategy to overcome major barriers in phototherapy and facilitate clinical translation.
Yadong Liu, Yifan Xue, Hongru Lin et al.· Acta Biomaterialia· 0 citations
