Covalent "Locking" of Prodrug Nanoassemblies via Thiol-Ene Click Crosslinking for Potent Antitumor Therapy

Prodrug nanoassemblies formed by the self-assembly of prodrugs represent an emerging platform, offering advantages such as high drug loading, facile preparation, and tumor selectivity. However, existing prodrug nanoassemblies primarily depend on noncovalent intermolecular interactions to maintain structural integrity, rendering them vulnerable to in vivo instability and severely constraining their clinical translation. To overcome those limitations, we introduce a mild and efficient thiol-ene click reaction to construct prodrug nanoassemblies reinforced by a covalently crosslinked network. Specifically, prodrugs are designed by conjugating cabazitaxel (CTX) to tri-alkene-containing side chains via tumor redox-responsive bonds. These prodrugs spontaneously assemble into nanoassemblies enriched with surface-exposed olefin groups, which are subsequently "locked" by covalent crosslinking using tetra-arm thiol crosslinkers. The resulting covalently crosslinked prodrug nanoassemblies exhibit markedly improved stability, leading to prolonged systemic circulation and enhanced tumor accumulation, thereby translating into superior antitumor efficacy. Moreover, the redox-cleavable bond enables tumor microenvironment-responsive drug release, effectively mitigating the systemic toxicity of CTX while preserving its antitumor potency. Collectively, this covalent "locking" strategy provides a notable advancement in optimizing the structural stability of prodrug nanoassemblies and offers a promising strategy for developing novel chemotherapeutic delivery platforms that integrate circulatory stability with tumor selectivity.