Abstract / Summary
Acquired cisplatin resistance remains a major challenge in cancer therapy and is frequently associated with enhanced RAD51-mediated homologous recombination (HR) repair. Here, we identify the CD2 domain of the pluripotency factor NANOG as a previously unrecognized inhibitor of HR repair. Mechanistically, the CD2 peptide interacts with RAD51, thereby impairing nucleofilament assembly and limiting the repair of DNA double-strand breaks. To facilitate intracellular delivery of this macromolecular cargo, we engineered a cell-penetrating peptide (CPP)-functionalized ZIF-8 nanoplatform. This nanosystem promoted cellular uptake, endosomal escape, and subsequent nuclear localization of CD2. Importantly, the truncated CD2 fragment retained HR-inhibitory activity while lacking the transcriptional domains present in full-length NANOG that are associated with stemness-related and oncogenic functions. Functionally, intracellular delivery of CD2 suppressed HR repair activity and enhanced cisplatin sensitivity in both parental and cisplatin-resistant cervical cancer cells. Upon cisplatin treatment, the nanoplatform increased DNA damage and apoptotic responses, leading to greater cytotoxic effects in vitro . Collectively, these findings demonstrate that combining endogenous protein–protein interaction modulation with nanodelivery strategies represents a feasible approach for targeting HR repair and improving cisplatin responsiveness in cervical cancer cells.