Polyphenol-Based Nanoparticles for Intracellular Protein Delivery via Competing Supramolecular Interactions

Intracellular delivery of proteins is a promising strategy for regulating cellular behavior and therefore has attracted interest for biomedical applications. Despite the emergence of various nanoparticle-based intracellular delivery approaches, it remains challenging to engineer a versatile delivery system capable of responding to various physiological triggers without the need for complex chemical synthesis of the delivery system. Herein, we develop a template-mediated supramolecular assembly strategy to synthesize protein-polyphenol nanoparticles (NPs) capable of endosomal escape and subsequent protein release in the cytosol. These NPs are stable in serum and undergo surface charge reversal from negative to positive in acidic environments, leading to spontaneous endosomal escape. In the cytosol, endogenous small peptides and amino acids with relatively high charge densities, such as glutathione, trigger NP disassembly through competitive supramolecular interactions, thereby releasing functional bioactive proteins, as validated using cytochrome C and β-galactosidase. The versatility of the present strategy in terms of nanoparticle size, protein type, and functional protein delivery makes this a promising platform for potential application in the field of protein therapeutics.