A selective RCC1 inhibitor loaded in membrane-coated DNA nanocage for targeted suppression of TNBC progression

Triple-negative breast cancer (TNBC) exhibits high recurrence rate and worse prognosis because of lacking effective targeted therapy. In this study, RCC1 was found to be highly expressed in TNBC and contribute to poor prognosis by promoting tumor progression through activation of Notch1 signaling pathway, suggesting that RCC1 is a potential therapeutic target for TNBC. Subsequently, Euphorbiasteroid (Ebd) was identified as a potent small-molecule inhibitor of RCC1 protein by high-throughput screening and can significantly suppress TNBC tumor growth and metastasis. To overcome the poor bioavailability and off-target effects of Ebd, a biomimetic nanodrug delivery system (TPRDN) was developed. Ebd was encapsulated within tetrahedral DNA nanocages assembled from four DNA oligonucleotide chains. These DNA nanocages were then coated with hybrid membranes composed of TNBC cell, platelet, and red blood cell membranes. Additionally, a Nectin-4 targeting bicyclic peptide was functionalized on the hybrid membranes to improve targeting precision. The TPRDN system can significantly target TNBC tissues and circulating tumor cells, thereby enhancing the inhibitory effects of Ebd on TNBC growth and metastasis, highlighting a promising strategy for precise and effective treatment for TNBC.