CDCA7–CD44 target pair drives precision elimination of drug-tolerant persister cells in breast cancer

Drug resistance and recurrence remain the major causes of poor prognosis in breast cancer, driven by a small subset of drug-tolerant persister (DTP) cells that survive chemotherapeutic stress. We identified cell division cycle-associated protein 7 (CDCA7) as a key driver of survival and drug tolerance in breast cancer DTP cells, highlighting it as a potential intracellular therapeutic target. However, targeted therapies against DTP cells face challenges due to off-target effects and on-target toxicities, which may compromise the efficacy of CDCA7-directed interventions. Integrated analysis of clinical samples and multi-omics datasets further revealed that the membrane receptor CD44 was co-upregulated with CDCA7 in DTP cells, serving as a distinct recognition site for targeted delivery. Based on these findings, we developed a lipid nanoparticle (LNP) delivery system that leverages the CDCA7–CD44 target pair to enable CD44-mediated selective recognition and endocytosis by DTP cells, thereby co-delivering siCDCA7 and epirubicin (EPI) to efficiently eliminate DTP cells and effectively reverse drug tolerance. This study highlights the pivotal role of the CDCA7–CD44 target pair in DTP biology and establishes a novel strategy for precision therapy against drug-resistant breast cancer. CDCA7 drives breast cancer DTP chemoresistance via CHK2 . Co-upregulated CD44 enables targeted HA-LNP co-delivery of siCDCA7 and epirubicin, eliminating DTP cells and restoring chemosensitivity.