RBCM/ZIF-8 biomimetic nano-delivery system to improve anti-resistant breast tumor efficacy by synergistic cuproptosis effect and multiple strategies

Chemotherapy drugs are often associated with toxic side effects and low bioavailability, while solid tumors like breast cancer frequently exhibit multidrug resistance, which limits the clinical efficacy of chemotherapy and other monotherapies. To address these challenges, there is a need for the development of efficient delivery systems capable of transporting various therapeutic agents while introducing novel programmed death mechanisms to achieve synergistic antitumor effects. In this study, zeolite imidazole-8 (ZIF-8) was utilized as a core carrier to load doxorubicin (DOX) and photothermal agent CuS, and further coated by folic acid (FA)-functionalized red blood cell membranes (RBCM) to fabricate the FRCZD delivery system. This system possessed the capacity to target breast cancer MCF-7 cells and their drug-resistant strain, MCF-7/ADR cells. Notably, DOX and CuS were rapidly released in response to both the tumor microenvironment (TME) and near-infrared radiation (NIR). Under light stimulation, CuS induced photothermal therapy (PTT), which further enhanced localized drug accumulation while catalyzing H 2 O 2 to produce toxic hydroxyl radicals (⋅OH) that triggered chemodynamic therapy (CDT). Moreover, excessive intake of Cu 2+ led to mitochondrial metabolic dysfunctions that ultimately initiated cuproptosis. The results demonstrated that FRCZD combined with NIR accelerated cell apoptosis while interfering with cell cycle distribution, consequently inhibiting tumor cell proliferation and migration. In vivo experiment results further corroborated that FRCZD + NIR significantly inhibited tumor growth more effectively than other experimental groups while exhibiting favorable biological safety profiles. Overall, the integrated platform FRCZD could substantially enhance treatment outcomes by inducing cuproptosis in conjunction with chemotherapy, PTT, and CDT approaches, thus holding promise for advancing therapies against drug-resistant tumors.