Site-specific engineering of S-Te-S bridged nano-prodrug: A dual equilibrium strategy for enhanced antitumor efficacy and safety of paclitaxel.

Homodimeric prodrug nanoassemblies (HPNs) have emerged as an effective strategy to enhance the therapeutic efficacy and safety of chemotherapeutic drugs. However, achieving both stable assembly and rapid drug release in tumor remains a critical challenge. Herein, we designed S-Te-S linkages with varying linkage lengths (α-, β-, and γ-) to develop three paclitaxel (PTX) homodimeric prodrug nanoassemblies (PHPNs). Notably, α-PHPNs demonstrated superior assembly stability and fast drug release rate under tumor microenvironment stimulation. Our study successfully develops α-position PHPNs achieving dual balance through: (1) optimized assembly ability via equilibrium between driving forces and "structural defects", and (2) coordinated management of blood long-circulation and tumor-specific activation for superior efficacy and safety. Our investigation elucidates how linkage length influences both assembly performance and activation efficiency in triatomic hybrid chalcogen bonds and elucidates the oxidation-responsive release mechanism of S-Te-S bonds. These findings advance prodrug nanoassemblies design principles and establish theoretical foundations for the application of hybrid bond in cancer treatment.