Dilemma-Solving PIC Vesicles: Ligand-Driven Assembly of Stable yet Degradable Nanocarriers for Cytosolic Protein Delivery

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.