α-Amino acid N-carboxyanhydride (NCA)-derived synthetic polypeptides for nucleic acids delivery

In recent years, gene therapy has come into the spotlight for the prevention and treatment of a wide range of diseases. Polypeptides have been widely used in mediating nucleic acid delivery, due to their versatilities in chemical structures, desired biodegradability, and low cytotoxicity. Chemistry plays an essential role in the development of innovative polypeptides to address the challenges of producing efficient and safe gene vectors. In this Review, we mainly focused on the latest chemical advances in the design and preparation of polypeptide-based nucleic acid delivery vehicles. We first discussed the synthetic approach of polypeptides via ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs), and introduced the various types of polypeptide-based gene delivery systems. The extracellular and intracellular barriers against nucleic acid delivery were then outlined, followed by detailed review on the recent advances in polypeptide-based delivery systems that can overcome these barriers to enable in vitro and in vivo gene transfection. Finally, we concluded this review with perspectives in this field.