A molecularly engineered rhenium platform triggers a self-enhancing RNS storm to disrupt tumor hypoxia and resultant immunosuppression
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.