Reversing Cuproptosis Tolerance with Twinborn Metallic Polymer Nanoparticles for Enhancing Efficacy of Chemo-Immunotherapy

Cuproptosis is a new form of regulated cell death that might help overcome chemotherapy resistance. However, its therapeutic efficacy is significantly undermined by the aberrant activation of the Wnt/β-catenin pathway, conferring an intrinsic tolerance that necessitates innovative strategies. Herein, guided by bioinformatic analysis and prior studies that stated that cisplatin might suppress Wnt signaling via p53-mediated upregulation of RARRES3, a twinborn metallic polymer P(Pt–Cu)-based nanoparticle NP(Pt–Cu) was developed. P(Pt–Cu) was obtained by copolymerization from a cuproptosis inducer (TriPy-Cu) with oxidized cisplatin (Pt (IV)) in an optimized ratio. It was then coassembled with a reactive oxygen species (ROS)-responsive polymer, PHPM, to form NP(Pt–Cu). The incorporation of both Cu and Pt components into the polymer backbone rendered NP(Pt–Cu) with the on-demand release of copper ions and cisplatin, thereby synergizing cuproptosis with chemotherapy. Additionally, NP(Pt–Cu) acted as a type II immunogenic cell death (ICD) inducer, suppressing the Wnt/β-catenin pathway via endoplasmic reticulum (ER) stress-triggered Ca 2+ overload. In vivo studies of an orthotopic triple-negative breast cancer (TNBC) mouse model demonstrated the superior tumor suppression and immune activation of NP(Pt–Cu) over monotherapies. Overall, this work not only addresses cuproptosis tolerance via Wnt pathway inhibition but also provides a potent chemo-immunotherapeutic strategy for aggressive cancers.