A Lactose-Derived CRISPR/Cas9 Delivery System for Efficient Genome Editing In Vivo to Treat Orthotopic Hepatocellular Carcinoma

Gene editing is a crucial and effective strategy to treat genetic diseases. Safe and effective delivery vectors are specially required for efficient gene editing in vivo of CRISPR/Cas9 system. Interestingly, lactose, a natural saccharide, can specifically bind to asialoglycoprotein receptors, highly expressed on the surface of hepatocellular carcinoma (HCC) cells. Herein, a lactose-derived branched cationic biopolymer (LBP) with plentiful reducible disulfide linkages and hydroxyl groups is proposed as a potential delivery vector of CRISPR/Cas9 system for efficient genome editing in vivo to treat orthotopic HCC. LBP is synthesized via a facile one-pot ring-opening reaction. LBP possesses excellent compacting ability, degradability, biocompatibility, gene transfection performances, and HCC-targeting ability. LBP-mediated delivery of classical pCas9-survivin, which can target and knockoutsurvivinoncogene, produces efficient gene editing performances, and superb anti-cancer activities in orthotopic HCC mouse models. This study provides an attractive and safe strategy for the rational design of CRISPR/Cas9 delivery system.