Combinative dual-nanoparticle assembly improves oxygen-autarky PDT efficacy in hypoxic tumors

O 2 -dependent photodynamic therapy (PDT) represents an efficient strategy for tumor ablation, but its therapeutic efficacy is critically compromised in hypoxic tumors. To tackle unsatisfying O 2 supplying, we design a dual-nanoparticle assembly for O 2 source-carrying photosensitizer delivery to enhance PDT efficiency. Structurally, catalase (CAT) is condensed into nanocapsules for biostability and sustainable O 2 supplying, and indocyanine green (ICG) is dispersed in polymeric nanospheres to prevent photobleaching and self-aggregation. According to O 2 demands, CAT nanocapsules are covalently conjugated with ICG nanospheres in an optimal ratio to facilitate O 2 enrichment around photosensitizer, together with hyaluronic acid (HA) decoration for advanced tumor targeting, thereby achieving O 2 -autarky PDT in hypoxic tumors. In comparison to simply-mixed delivery of CAT nanocapsules and ICG nanospheres, dual-nanoparticle assembly enables co-accumulation of CAT and ICG at the tumor site via HA receptor recognition, followed by CAT-catalyzed O 2 -generation and in situ O 2 -supplying to the surrounded ICG nanospheres, thereby satisfying O 2 demands of hypoxic tumors during PDT. Consequently, the nanoassembly significantly increases the intra-tumoral oxyhemoglobin saturation to 31.68% and yields tumor inhibition of 85.94% in the orthotopic breast cancer models. Collectively, this study provides a dual-nanoparticle assembly design of O 2 source-carrying photosensitizer to achieve O 2 -autarky PDT and establishes a new paradigm for O 2 -dependent PDT in hypoxic tumors.