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 H₂O₂ into O₂. However, the effectiveness of this strategy is limited by the insufficient concentration of H₂O₂ in the tumor microenvironment (TME). Herein, we developed a H₂O₂ economizer for on-demand O₂ 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 H₂O₂ 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 H₂O₂. Ultrasound irradiation promoted MFC dissociation and the exposure of Fe-PDAP for a more robust O₂ 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 H₂O₂ economizer significantly alleviates tumor hypoxia via reducing H₂O₂ expenditure and that on-demand oxygen-elevated sonodynamic immunotherapy can effectively combat tumors.