Charge-reversal nanocomolexes-based CRISPR/Cas9 delivery system for loss-of-function oncogene editing in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. There are still challenges for HCC treatments, especially high resistance of the cancer cells to chemotherapy and/or target therapy. In this study, a responsive charge-reversal vehicle consists of negatively charged heparin core and positively charged ethanolamine (EA)-modified poly(glycidyl methacrylate) (PGEA) shell (named Hep@PGEA) with self-accelerating release for condensed nucleic acids was proposed to deliver the pCas9 plasmid encoding clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) and the sgRNA targeting oncogene survivin to treat HCC. The Hep@PGEA/pCas9 system showed high anti-tumor efficiency via inducing apoptosis and inhibiting proliferation, migration and invasion capability of HCC cells. The Hep@PGEA/pCas9 system was further utilized to treat orthotopic HCC in mice via tail vein injection. The system exhibited an evident accumulation in the liver of mice and achieved obvious anti-tumor effects. The Hep@PGEA/pCas9 system also showed marked improvement of HCC therapy with sorafenib and provided promising combination HCC treatment potentials. Moreover, enrichment of the Hep@PGEA-based delivery system in liver highlights its possibilities for treatments of other liver diseases.