Biomimetic MOFs nanoparticles Co-delivering oridonin and siRNA for synergistic therapy in melanoma via ferroptosis pathway

ABSTRACT Malignant melanoma (MM) exhibits clinical traits of vigorous metastasis and an unfavorable prognosis. Traditional therapeutic modalities such as surgical resection, radiotherapy, and chemotherapy have restricted efficacy and notable side effects, thereby urgently demanding new drugs or treatment approaches. The iron-doped zeolite imidazole ester skeleton material (Fe-ZIF-8, FZ) exhibits outstanding biological safety and acid-responsive drug release properties, serving as an excellent nano-delivery carrier. Oridonin (Ori) is capable of inducing ferroptosis in tumor cells by targeting key genes (such as GPX4, SLC7A11, GGT1), and demonstrates a potent therapeutic effect on MM. Simultaneously, small interfering RNA (siRNA) can exert a role in gene silencing. In this study, we devised biomimetic nanoparticles (NPs) based on iron-doped zeolitic imidazolate framework-8 (FZ) for the co-delivery of Ori and siRNA targeting GPX4 (siRNA GPX4 ). FZ was employed to co-load Ori and siRNA targeting GPX4, the core regulator of ferroptosis, to play a role in drug and gene therapy for MM. The A375 tumor cell membrane was biomimetically modified to construct anti-tumor drug targeted delivery nanoparticles, thereby achieving efficient co-delivery of Ori and siRNA GPX4 . This provides a novel idea for the development of highly efficient and low-toxicity treatment of MM and the overcoming of tumor drug resistance.