Dual-Responsive Biomimetic Nanoplatform for Cascade Synergistic Therapy of Endometrial Cancer

Abstract

Endometrial cancer is a common malignant tumor in the female reproductive system. Traditional chemotherapy has limitations such as poor targeting, dose-limiting toxicity, and treatment intensity restrictions. To address these issues, this study constructed an intelligent nanoplatform–GOD-Fe3+&DOX-Membrane@Polymer (GOD-Fe3+&DM@Poly.)–based on reversible addition-fragmentation chain transfer (RAFT) polymerization technology. The incorporation of pyridine disulfide bonds as polymer side chains through RAFT polymerization facilitated the precise covalent immobilization of glucose oxidase (GOD), effectively mitigating the leakage issues commonly observed with physical encapsulation methods. Concurrently, benzylboronic acid moieties were integrated into the polymer backbone, enabling the formation of reversible borate ester linkages with sialic acid residues present on the membranes of HEC-1A cancer cells. This interaction promoted homologous targeting and substantially improved their intratumoral enrichment efficiency. In addition, GOD-mediated starvation therapy and Fe3+-triggered chemodynamic therapy construct a cascade reaction: GOD consumes tumor glucose to produce H2O2, which is converted into highly toxic hydroxyl radicals through the Fe3+-mediated Fenton reaction, amplifying tumor oxidative stress to initiate ferroptosis. This integration establishes a valuable technical framework for the development of multifunctional and stimuli-responsive nanomedicines.