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.