Polyion complex (PIC) vesicles represent a promising platform for protein therapeutics delivery, yet balancing extracellular stability with intracellular degradability remains challenging. Herein, we present a ligand-engineering strategy to fabricate dual-functional PIC vesicles. The design centers on a disulfide bridged bis-dipicolinic acid ligand, L2(S-S), which chelates with Gd3+ at a stoichiometric ratio of 1:3 to form anionic branched coordination polymers. These polymers coassemble with cationic PEG113-b-PMETAC73 diblock copolymers, creating uniform vesicles capable of in situ protein loading while preserving their structure and bioactivity. The branched architecture ensures extracellular stability of the vesicle and effective cargo shielding. However, upon cellular internalization, the high intracellular glutathione concentration triggers the reductive cleavage of disulfide bonds, leading to rapid polymer degradation, vesicle disassembly, and subsequent cytoplasmic protein release. Notably, while both GSH-responsive and nonresponsive vesicles facilitated efficient cytosolic delivery, only the degradable vesicles induced significant tumor suppression, underscoring the critical role of cytoplasmic protein release for therapeutic efficacy. This ligand-engineering approach resolves the stability-degradability paradox and provides a general design principle for intelligent protein delivery systems.
Yu et al. (Mon,) studied this question.