The outcome of sonodynamic immunotherapy is significantly limited by tumor hypoxia. To overcome this obstacle, one common solution is to catalyze the conversion of endogenous H 2 O 2 into O 2 . However, the effectiveness of this strategy is limited by the insufficient concentration of H 2 O 2 in the tumor microenvironment (TME). Herein, we developed a H 2 O 2 economizer for on-demand O 2 supply and sonosensitizer-mediated reactive oxygen species production during ultrasound activation, thereby alleviating hypoxia-associated limitations and augmenting the efficacy of sonodynamic immunotherapy. Methods: The H 2 O 2 economizer is constructed by electrostatic adsorption and π-π interactions between the Fe-doped polydiaminopyridine (Fe-PDAP) nanozyme and chlorin e6. By employing a biomimetic engineering strategy with cancer cell membranes, we addressed the premature leakage issue and increased tumor-site accumulation of nanoparticles (membrane-coated Fe-PDAP/Ce6, MFC). Results: The prepared MFC could significantly attenuate the catalytic activity of Fe-PDAP by reducing their contact with H 2 O 2 . Ultrasound irradiation promoted MFC dissociation and the exposure of Fe-PDAP for a more robust O 2 supply. Moreover, the combination of MFC-enhanced sonodynamic therapy with anti-programmed cell death protein-1 antibody (aPD-1) immune checkpoint blockade induced a strong antitumor response against both primary tumors and distant tumors. Conclusion: This as-prepared H 2 O 2 economizer significantly alleviates tumor hypoxia via reducing H 2 O 2 expenditure and that on-demand oxygen-elevated sonodynamic immunotherapy can effectively combat tumors.

This study provides an efficient theranostic strategy for concurrent targeted ultrasound molecular imaging and effective synergistic antitumor therapy.

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