Lu Jiang, Qiantao Song, Zhixing Lin, Hai Liu, Jingqu Chen, Xi Zhang, Hui Li, Christina Cortez-Jugo, Jiajing Zhou, Lu Liu, Frank Caruso, Hejin Jiang
Precise intracellular delivery remains a critical barrier to the efficacy of therapeutic biomolecules. Coacervates, with their high loading capacity, have emerged as a transformative drug delivery platform that can facilitate the intracellular delivery of diverse therapeutic cargos but are limited by poor stability, nonspecific cellular internalization, and uncontrolled release. Herein, we report a simple and versatile surface-engineering strategy that improves the stability of coacervates and enables programmable cell targeting and precise intracellular delivery. Peptide coacervates (PCs) designed with programmable release were coated with polyphenol-peptide networks (PC@PPNs) to encapsulate diverse cargos, including fluorophores, toxic proteins, pro-apoptotic peptides, and plasmid DNA. The dual pH- and glutathione-responsive disassembly of PC@PPNs facilitates endosomal escape and enables controlled cytosolic release. Notably, the association of PC@PPNs with specific cells can be readily programmed by modulating the peptide sequence on PPNs. For example, incorporating HER2-targeting peptides increases the specific association of PC@PPNs with SKOV3 cells from 14% to 75%. The cell-specific targeting is further validated in vivo, as demonstrated by a pronounced size reduction in HER2-overexpressing tumors. This work establishes a rational framework for engineering functional coacervates, advancing their development as versatile and programmable platforms for intracellular delivery.