Robust antitumor treatment driven by lock-and-key biorecognition of dynamic cyclic diselenide-guided chiral prodrug self-assembly

Designing highly selective nanomedicines with precise recognition of biological interfaces for efficient cancer therapy represents a tremendous challenge. Inspired by the inherent chirality and enantioselectivity of organisms, we constructed dynamic chiral cyclic diselenide-conjugated paclitaxel prodrug nanoassemblies (CSEPNs) to simulate the chiral recognition process. The optimal chiral configuration with potent antitumor effects was screened by deconstructing the lock-and-key biorecognition of CSEPNs. Compared with R-(−)-CSEP, S-(+)-CSEP displayed steady chirality-dependent self-assembly due to the balance of intermolecular interaction and steric hindrance. With ring-tensioned backbone and superior chiral topology, S-(+)-CSEPNs exhibited ultra-high redox sensitivity and enhanced clathrin-mediated endocytosis. More importantly, S-(+)-CSEPNs presented the in vivo transport advantages of high tumor accumulation and low excretion rate. Finally, CSEPNs exerted robust synergistic tumor suppression through chemotherapy, tumor redox axis modulation, and tumor angiogenesis inhibition. These findings confirmed the dominant role of chiral lock-and-key biorecognition in determining the biological fate of the nanomedicines.