A mitochondrion-targeted natural polyphenolic copper carrier overcomes tumor resistance to cisplatin by potentiating cuproptosis

Platinum-based drug resistance remains a major obstacle in cancer therapy. Cuproptosis, a novel form of copper-dependent cell death regulated through mitochondrial pathways, represents a promising strategy to counteract drug resistance in tumors. However, its efficacy is constrained by several physiological barriers, including elevated intracellular glutathione (GSH) levels, inadequate copper accumulation both cytoplasmically and within mitochondria, and the overexpression of copper efflux transporters such as ATP7A/B. To overcome these limitations, we developed a mitochondrion-targeted polyphenol–copper nanocarrier (denoted bm–Cur–Cu₃@RBCm, or bCCM) by chelating Cu(II) with bisdemethylcurcumin—a tridentate ligand offering three copper-binding sites—and encapsulating the complex within red blood cell membranes (RBCm). This system enhances cuproptosis and counteracts drug resistance through three synergistic mechanisms. First, it significantly increases intracellular copper delivery via high-capacity tridentate chelation while concurrently depleting GSH to prevent the formation of inert GSH–Cu/Pt complexes, thereby increasing the bioavailability of copper and cisplatin. Second, it promotes mitochondrial copper accumulation through targeted delivery and localized GSH depletion, leading to irreversible mitochondrial damage. Third, it downregulates ATP7B expression, thereby inhibiting copper and cisplatin efflux and enhancing both cuproptosis and chemosensitivity. In vitro and in vivo evaluations demonstrated that bCCM effectively targets tumor cells and exerts potent antitumor activity against cisplatin-resistant hepatocellular carcinoma (HCC) without inducing systemic toxicity or undesirable copper accumulation. Mechanistic studies confirmed that bCCM downregulates key proteins associated with both cuproptosis and cisplatin resistance, indicating effective synergy between cuproptosis and conventional chemotherapy. This work establishes bCCM as an innovative therapeutic platform for overcoming platinum-based chemotherapy resistance, with promising potential for clinical translation in oncology.