Biomineralized Multienzyme‐Mimicking 2D Nanoplatform Achieves Efficient Redox‐Governed Reversal of Tumor Multidrug Resistance

ABSTRACT Multidrug resistance (MDR) in cancer is driven by hypoxia, elevated antioxidant capacity, and drug efflux. Herein, a universal MDR‐reversal nanoplatform based on hyaluronic acid (HA)‐templated manganese oxide nanosheets (MH NSs) was developed through a biomineralization strategy. The coexistence of Mn(II)/Mn(III)/Mn(IV) endows MH NSs with coordinated multienzyme‐like reactivity, including peroxidase (POD)‐like ROS amplification, glutathione oxidase (GSHOx)‐like redox disruption, and catalase (CAT)‐like hypoxia relief, which collectively remodel the tumor microenvironment and dismantle MDR defenses. The platform exhibits broad drug‐loading compatibility through multiple interactions, including electrostatic binding, metal‐ligand coordination, and hydrophobic encapsulation. Using doxorubicin (DOX) as a model drug, DOX‐loaded MH NSs (MH‐DOX) achieve CD44‐targeted delivery, clathrin‐mediated endocytosis, and evasion of efflux clearance. Mechanistically, the CAT‐like activity of MH NSs relieves hypoxia and suppresses the HIF‐1α/MDR1/P‐gp axis, the POD‐like catalysis enhances ROS accumulation to activate the apoptotic cascade, and the GSHOx‐like function depletes intracellular GSH and inhibits GPX4 to induce ferroptosis. Notably, MH NSs supports DOX intersystem crossing, enabling ultrasound‐triggered production of 1 O 2 and ·OH. Acting in concert with the redox cascades, MH‐DOX synergistically overcomes MDR barriers, enabling dual apoptosis‐ferroptosis induction and significantly enhancing DOX sensitivity. Collectively, MH NSs represent a programmable nanozyme platform broadly applicable to redox‐regulated drug delivery and resistance modulation.