NIR light-driven photocatalytic NAD(P)H oxidation and H2O2 generation in situ for enhanced chemodynamic therapy and immune response

Chemodynamic therapy (CDT) is an appealing cancer treatment that converts endogenous H2O2 into highly toxic hydroxyl radicals to kill cancer cells. However, the limited amount of H2O2 in tumor cells constrains the application of CDT. Therefore, the strategy that can increase H2O2 level in situ could broaden its clinical application. Herein, we synthesized a supramolecule [Ru(bpy)2(Nabpy)](PF6)2 (Ru1) which can efficiently photo-catalyze NAD(P)H oxidation with simultaneous generation of H2O2 with a high yield at 76.4 %. The Ru1 and Fe2+ were then loaded on the mesoporous silica-encapsulated rare earth-doped upconversion nanoparticles (UCSRF), the intracellular H2O2 level can be elevated by 2.8 times upon the irradiation of near-infrared (NIR) light irradiation. Then, the intracellular H2O2 was transformed into hydroxyl radicals through Fenton reaction to achieve efficient CDT both in vitro and in vivo. Furthermore, we demonstrated that UCSRF could effectively enhance immunogenic cell death (ICD) effect, resulting in the reprogramming of the immunosuppressive tumor microenvironment to stimulate immune response. This work represents the first proof-of-concept study on photo-catalytically enhancing H2O2 production in situ upon NIR irradiation for spatiotemporal CDT.