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 Ca2+ 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.