Dual regulation of osteosarcoma hypoxia microenvironment by a bioinspired oxygen nanogenerator for precise single-laser synergistic photodynamic/photothermal/induced antitumor immunity therapy.

The hypoxic tumor microenvironment (TME) of osteosarcoma (OS) is the Achilles' heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are confronted to reverse the hypoxia. Herein, we proposed a "reducing expenditure of O and broadening sources" dual-strategy and constructed ultrasmall IrO@BSA-ATO nanogenerators (NGs) for decreasing the O-consumption and elevating the O-supply simultaneously. As O NGs, the intrinsic catalase (CAT) activity could precisely decompose the overexpressed HO to produce O in situ, enabling exogenous O infusion. Moreover, the cell respiration inhibitor atovaquone (ATO) would be at the tumor sites, effectively inhibiting cell respiration and elevating oxygen content for endogenous O conservation. As a result, IrO@BSA-ATO NGs systematically increase tumor oxygenation in dual ways and significantly enhance the antitumor efficacy of PDT. Moreover, the extraordinary photothermal conversion efficiency allows the implementation of precise photothermal therapy (PTT) under photoacoustic guidance. Upon a single laser irradiation, this synergistic PDT, PTT, and the following immunosuppression regulation performance of IrO@BSA-ATO NGs achieved a superior tumor cooperative eradicating capability both and . Taken together, this study proposes an innovative dual-strategy to address the serious hypoxia problem, and this microenvironment-regulable IrO@BSA-ATO NGs as a multifunctional theranostics platform shows great potential for OS therapy.