A hydrogen peroxide economizer for on-demand oxygen production-assisted robust sonodynamic immunotherapy

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.