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. A series of material characterization techniques (FT-IR, UV-vis, XPS, ICP-MS, XRD, DLS, TEM) were employed to systematically characterize bCCM. At the cellular level, experiments including CCK-8 assay, live/dead staining via holographic microscopy, apoptosis/necrosis staining imaging, ROS staining imaging, copper ion imaging, mitochondrial co-localization imaging, mitochondrial membrane potential imaging, and JC-1 staining were performed on cisplatin-resistant hepatocellular carcinoma cells BEL7402/DDP. In animal models, further studies were conducted, such as small animal in vivo imaging, tissue copper content measurement, TUNEL assay, and immunohistochemistry (IHC). We have developed a mitochondria-targeted polyphenol-copper nanocarrier, bCCM, which operates through three synergistic mechanisms to enhance the efficacy of cisplatin-resistant hepatocellular carcinoma (HCC) therapy. First, it significantly increases intracellular copper delivery through high-capacity tridentate chelation while depleting glutathione (GSH) to prevent the formation of inert GSH-Cu/Pt complexes, thereby improving the bioavailability of both copper and cisplatin. Second, it promotes mitochondrial copper accumulation via targeted delivery and localized GSH depletion, leading to irreversible mitochondrial damage. Third, it downregulates ATP7B expression, inhibiting the efflux of copper and cisplatin, which further enhances intracellular copper retention and chemosensitivity. Both in vitro and in vivo evaluations demonstrate that bCCM effectively targets tumor cells, exerts potent antitumor activity against cisplatin-resistant HCC, and does not induce systemic toxicity or adverse copper accumulation. bCCM downregulates key proteins associated with cuproptosis and cisplatin resistance, demonstrating effective synergy between cuproptosis and conventional chemotherapy. This study establishes bCCM as an innovative therapeutic platform for overcoming platinum-based chemotherapy resistance, showing significant potential for clinical translation in oncology.