Defect Engineering of Biodegradable Sulfide Nanocage Sonozyme Systems Enables Robust Immunotherapy Against Metastatic Cancers

Abstract It is important but challenging to innovate inorganic sonosensitizers with controlled biodegradability and enhanced sonodynamic and chemodynamic activities to harness and remodel the immunosuppressive tumor microenvironment (TME) for awakening robust immune responses against metastatic cancers. Herein the rational design and defect engineering strategy of a pH‐responsive biodegradable sonozyme system in sulfide nanocages for augmented cancer immunotherapy is reported. A series of highly defective Co 9 S 8‐x sonosensitizers with elevated sulfur‐vacancy (V S ) levels are fabricated to systematically explore the V S ‐dependent sonodynamic and chemodynamic properties by regulating the weight ratio of the sulfur to cobalt source. The bandgap is substantially reduced from 2.06 to 1.54 eV, and the atomic ratio of Co 2+ to Co 3+ is increased from 1.53 to 1.97. Therefore, the sonodynamic, chemodynamic, and antitumor immune responses of Co 9 S 8‐x are dramatically augmented by defect engineering of a biodegradable sulfide sonozyme system. The slow degradation in the slightly acid TME substantially reduced the size for enhanced tumor targeting and infiltration, while exerting a slight influence on the sonodynamic performance. As a result, satisfactory therapeutic effects on the eradication of primary, distant, and metastatic tumors can be achieved. This work highlights the potential of defect engineering strategies in biodegradable sonosensitizers for enhanced immunotherapy in combating metastatic cancers.