Glucose transporter protein 1-targeted polymetallic coordination nanopolymer remodeled cisplatin-resistant microenvironment for enhanced chemotherapy of lung cancer.

Cisplatin (CDDP), a first-line chemotherapeutic agent, faces significant challenges in the treatment of non-small-cell lung cancer (NSCLC) due to the rapid emergence of drug resistance. In this study, a glucose transporter protein 1-targeted nanodrug (RCPM) was developed by coordinating rutin with polymetallic ions, including Fe, V, and Pt. RCPM selectively targeted CDDP-resistant A549 (A549R) cells, efficiently accumulating within tumors. Exhibiting exceptional photothermal (PT) properties, RCPM facilitated PT-induced tumor ablation. Within the tumor microenvironment, RCPM underwent degradation, releasing high concentrations of V, Fe, and CDDP. The liberated V and Fe ions catalyzed the Fenton reaction, generating reactive oxygen species (ROS) and inducing ferroptosis. Simultaneously, these metal ions synergistically suppressed the expression of excision repair cross-complementing 1 (ERCC1), glutathione (GSH), and adenosine triphosphate (ATP), effectively disrupting DNA repair pathways, preventing CDDP inactivation, and enhancing its cytotoxicity against A549R tumors. Furthermore, RCPM demonstrated complete and rapid renal clearance, ensuring excellent biosafety and strong clinical translational potential. In vivo studies revealed that a single administration of RCPM, combined with PT therapy, significantly inhibited NSCLC progression. These findings highlight RCPM as a promising nanodrug for overcoming CDDP resistance and enhancing NSCLC treatment efficacy.