Engineering an Ultrasound-Responsive Glycopolymersome for Hepatocyte-Specific Gene Delivery

The ability to design liver-targeted gene delivery vectors is plagued with difficulties ranging from carrier-mediated cellular toxicity to challenges in encapsulating sensitive nucleic acids. Herein, we present an ultrasound-responsive glycopolymersome strategy for <i>in situ</i> loading of nucleic acids and achieving hepatocyte-specific gene delivery. This glycopolymersome is self-assembled from a block copolymer, <i>N</i>-acetylgalactosamine-grafted poly(glutamic acid)-<i>block</i>-poly(ε-caprolactone) (PGAGalNAc-<i>b</i>-PCL). GalNAc is introduced to afford liver targeting through the selective binding to the asialoglycoprotein receptor overexpressed on hepatocytes. External ultrasound is utilized to assist in encapsulating nucleic acids within the hydrophilic lumen of glycopolymersomes by exploiting their ultrasound responsiveness nature. Biological studies confirmed the successful encapsulation of plasmid DNA (pDNA) and small interfering RNA (siRNA), rapid nuclear internalization, and efficient gene transfection. These findings collectively demonstrated that this ultrasound-responsive glycopolymersome could be exploited as a novel safe and efficient gene vector targeting hepatocytes.