The hypoxic and immunosuppressive tumor microenvironment limits photodynamic therapy (PDT). We designed a TME-responsive nanoplatform (Ir@MnO2@TK/FA) with MnO2 nanoshells, a perfluorocarbon (PFC)-modified iridium(III) photosensitizer (Ir-PFC), a reactive oxygen species (ROS)-responsive polymer, and a tumor-targeting folic acid ligand. MnO2 decomposes H2O2 to O2, and PFC stores O2, together alleviating hypoxia. Upon light irradiation, enhanced O2 boosts ROS generation via type I/II pathways. In vitro and in vivo studies show efficient O2 self-supply, multiple ROS production, potent cytotoxicity under hypoxia, and induction of necroptosis, pyroptosis, and immunogenic cell death. Released Mn2+ activates cGAS-STING. In vivo, the system relieves hypoxia and reverses immunosuppression. Overall, this work introduces an innovative nanoplatform that establishes a self-reinforcing cycle of hypoxia alleviation and immune activation, offering a potent combinatorial strategy to surmount PDT resistance and amplify antitumor immunity.
Peng Wang, Ying-Ying Han, Qing-Hua Shen et al.· Journal of Medicinal Chemist...· 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
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