A manganese-based biomimetic theranostic platform for "root-eradicating" strategy via pro-survival autophagy inhibition-enhanced synergistic antitumor therapy.

Abstract

Chemodynamic therapy (CDT) based on overproduced reactive oxygen species (ROS), activates cytoprotective autophagy, an inexorable phenomenon-that enables tumor cell survival, therefore attenuating ROS-induced therapeutic efficacy. Herein, we develop a tumor microenvironment (TME)-responsive nanoplatform (MnO_x-GOx-PM@Ma) composed of manganese oxide nanoflowers (MnO_x NFs) co-loaded with glucose oxidase (GOx) and an activatable melittin pro-peptide (PM), and coated with macrophage membranes (Ma) for targeted delivery. Combined MnO_x NFs and GOx trigger O₂/H₂O₂ cyclic generation, thereby amplifying CDT in the acidic and glutathione (GSH)-rich TME. Meanwhile, the PM is selectively cleaved by lysosomal legumain to activate melittin, which disrupts lysosomal membranes and converts cytoprotective autophagy into a pro-death process. Additionally, the releasing Mn²⁺ exhibits excellent magnetic resonance imaging (MRI) contrast properties. Both in vitro and in vivo studies demonstrate that MnO_x-GOx-PM@Ma effectively suppresses tumor growth through synergistic starvation therapy, enhanced CDT, and autophagy inhibition. Collectively, this work presents a strategy to overcome autophagy-mediated therapeutic resistance and optimize synergistic CDT-based antitumor therapy.