MnO2-coated CaO2 nanoparticles as pH-responsive oxygen self-sufficient carriers to potentiate radioimmunotherapy

Radioimmunotherapy represents a clinically available combination strategy for treating a broad range of solid tumors, however, its therapeutic efficacy remains significantly compromised by tumor hypoxia due to the inhibition of cytotoxicity and the suppression of antitumor immunity activation. Herein, we synthesized a pH-responsive oxygen-releasing nanomedicine (denoted as an oxygen nanotank) by growing a thin manganese dioxide (MnO 2 ) layer onto calcium hyperoxide (CaO 2 ) nanoparticles through an in-situ oxidation process to enhance radioimmunotherapy. Using a two-step liposomal coating strategy, we obtained CaO 2 @MnO 2 -PEG, which exhibited excellent physiological stability, with MnO 2 functioned as a catalase-like nanozyme to enable pH-dependent oxygen generation. This nanomedicine significantly enhanced the X-ray irradiation induced cytotoxicity against hypoxic tumor cells by amplifying intracellular reactive oxygen species. After intravenous injection, CaO 2 @MnO 2 -PEG specifically accumulated in tumor tissues and substantially alleviated hypoxia, resulting in enhanced therapeutic outcomes of X-ray-mediated external radiotherapy in a subcutaneous CT26 tumor model. Furthermore, combining CaO 2 @MnO 2 -PEG with immune checkpoint blockade therapy achieved synergistic tumor suppression by concurrently activating innate and adaptive immune responses. This study establishes a controllable synthesis method for pH-responsive oxygen nanotanks, effectively addressing hypoxia-induced therapeutic resistance in radioimmunotherapy.