Polyphenol-Mediated Nucleic Acid Complexation Generates Biofunctional Nanoparticles

Abstract

Nucleic acids play central roles in heredity, protein synthesis, and the regulation of cellular activities, inspiring the development of nanotechnology platforms to integrate and realize their biofunctionality. Desirable features for nucleic acid immobilization and biological applications include the loading of nucleic acids of varying sizes and structures, high biocompatibility, and mild fabrication conditions. Herein, we leverage the universal binding affinity of polyphenols and the cell-penetrating capability of cationic polypeptides to develop a versatile approach, whereby diverse types of nucleic acids are readily assembled into nanoparticles through complexation with polyphenols (e.g., tannic acid, TA) followed by capping with a cationic polypeptide (i.e., polyarginine, PArg). The nucleic acids include small-interfering RNA (siRNA), messenger RNA (mRNA), and plasmid DNA (pDNA). The TA–PArg–nucleic acid nanoparticles are primarily stabilized by hydrophobic interactions and electrostatic interactions, enabling a nucleic acid encapsulation efficiency of up to ∼90%. The nanoparticles also display cell-binding affinity, pH-responsiveness, and buffering capacity. These features collectively enable efficient cell internalization of the nanoparticles, pH-responsive release of nucleic acids (e.g., 74% mRNA release at pH 4 vs <20% at pH 7), and endosomal escape, resulting in robust intracellular transfection of siRNA, mRNA, and pDNA. This work provides a pathway to integrate genetic components into polyphenol networks, paving the way for advances in both fundamental and applied research on hybrid biofunctional nanoparticles.