Dual Enzyme-Loading MnO₂ Nanosystem for Cascade Chemodynamic Therapy With Enhanced Penetration in Superficial Tumors

The therapeutic effectiveness of superficial tumors is currently limited by the operational difficulty of traditional surgery. Localized target delivery of nanomedicine provides a promising solution for superior antitumor effect in superficial tumors, but its delivery efficiency can be greatly hampered by the dense tumor stroma. Compared with external modulation against the tumor extracellular matrix by physical methods, internal regulation of the tumor microenvironment via enzyme enables more direct degradation of the tumor extracellular matrix and robust antitumor efficacy. Herein, we report a dual-enzyme delivery nanoplatform to impart a cascade catalytic reaction for potent chemodynamic therapy with enhanced penetration depth in the superficial tumor. In response to the tumor microenvironment, the glucose oxidase/papain complex loaded in MnO₂ nanoparticles could be rapidly released to trigger cascade chemodynamic therapy and grant deeper penetration of therapeutic effect in the superficial tumor. The collective actions of papain's protease and peroxidase-like activity allowed significant tumor penetration and reactive oxygen species production cascaded with glucose oxidase, holding great promise as a potential strategy to improve the efficacy of superficial tumor treatment.