Fluorinated Acid‐Labile Branched Hydroxyl‐Rich Nanosystems for Flexible and Robust Delivery of Plasmids

Nucleic acid‐based therapy specially needs a safe and robust delivery vector. Herein, a novel fluorinated acid‐labile branched hydroxyl‐rich polycation (ARP‐F) is proposed for the flexible and effective delivery nanovector of different plasmids including reporter genes and the Cas9 plasmid. Acid‐responsive polycation (ARP) with plentiful ortho ester linkages and hydroxyl groups is first synthesized via a facile one‐pot ring‐opening polymerization, followed by decoration of fluorinated alkyl chains onto ARP to achieve ARP‐F. ARP‐F possesses good pH‐responsive degradability, biocompatibility, and its preliminary transfection ability evaluated by reporter plasmids pRL‐CMV (encoding Renilla luciferase) and pEGFP‐N1 (encoding enhanced green fluorescent protein) is also excellent. CRISPR‐Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR‐associated nuclease 9) technology is a potent genome‐editing tool. The subsequent delivery of pCas9‐surv (one typical all‐in‐one Cas9 plasmid) mediated by ARP‐F exhibits impressive in vitro and in vivo tumor inhibition performances. In addition, the combination of ARP‐F/pCas9‐surv with temozolomide could further enhance tumor inhibition activities by increasing the sensitivity of cancer cells to anticancer drugs. Such high‐performance polycation would provide a very promising means to produce efficient delivery nanovectors of versatile plasmids. A novel fluorinated acid‐labile branched hydroxyl‐rich nanovector is proposed for the safe and robust delivery of plasmids.