Atomic-valence engineering of a Mn(III)-tuned sonozyme system for multimodal tumor immunotherapy

The design of biodegradable multimodal nanomedicines such as sonozymes is indispensable for clinical applications. It is thus required to develop NIR-fluorescence imaging technologies allowing for in-time monitoring of their metabolic dynamics in vivo for spatiotemporally precise treatments owing to their unpredictability in vivo degradation dynamics. To this end, a biodegradable Mn (III)-based sonozyme in the MnO₂γ-phase was synthesized by atomic valence engineering (AVE) strategy based on hydrolysis and dismutation of Mn (III) ions. This synthetic strategy can tune the Mn (III) content from 70 % to 82 % and thus oxygen vacancy (V_O) concentration at room temperature via charge compensation. As a result, V_O-enhanced sonodynamic and nanozyme effects were observed. Moreover, NIR-fluorescent carbon dots (NIR-CDs) were in-situ assembled on the nanoflower surface by forming Mn (III)-N complexes, which quenched the fluorescence. In vitro and in vivo fluorescence imaging showed tumor-specific degradable dynamics owing to the biodegradation triggered by GSH overexpressed in the tumor microenvironment. Enhanced sonodynamic immunotherapy efficacy against both local and distant tumors was achieved by the synergism of V_O-mediated sonodynamic enhancement, Mn (III)-mediated GSH depletion, hypoxia alleviation and STING activation. Our results revealed that the Mn (III)-regulated nanozyme system as a biodegradable "all in one" theranostic platform can facilitate spatiotemporally controlled NIR imaging guided multimodal treatments in combating metastatic cancers.