One ternary nucleic acid delivery system with smart dextran-peptide coating enables in vivo and ex vivo wound therapy

•Dextran-peptide conjugate (Dex-H2E5) is prepared by a highly reproducible reaction •A ternary gene delivery system (HPD) is developed with smart Dex-H2E5 coating •HPD realizes high transfection in primary cells and favorable dosage independence •HPD succeeds in the in vivo and ex vivo gene therapy of full-thickness skin defects Apart from the superiority in supplementing cytokines in wound healing, gene therapy faces several critical obstacles, including the substantial exudation in wounds and difficult-to-transfect primary cells. Herein, a ternary nucleic acid delivery system (HPD) was constructed through the assembly of polyhexamethylene biguanide, DNA, and dextran-peptide conjugate (Dex-H2E5), which are prepared by the highly reproducible reaction of dextran and peptide. The proposed Dex-H2E5 forms a smart coating of HPD and acts as the “propellant” for the nucleic acid delivery. In vitro results confirmed that HPD realized low toxicity and high transfection performance in cell lines/primary cells and favorable serum stability/dosage independence. In vivo and ex vivo therapy of severe skin wounds further demonstrated the excellent performance of HPD after loading a therapeutic plasmid. Our work offers a highly efficient, reproducible delivery system for wound gene therapy. It could be extended to other clinical scenarios in which superior gene therapy is urgently demanded. Apart from the superiority in supplementing cytokines in wound healing, gene therapy faces several critical obstacles, including the substantial exudation in wounds and difficult-to-transfect primary cells. Herein, a ternary nucleic acid delivery system (HPD) was constructed through the assembly of polyhexamethylene biguanide, DNA, and dextran-peptide conjugate (Dex-H2E5), which are prepared by the highly reproducible reaction of dextran and peptide. The proposed Dex-H2E5 forms a smart coating of HPD and acts as the “propellant” for the nucleic acid delivery. In vitro results confirmed that HPD realized low toxicity and high transfection performance in cell lines/primary cells and favorable serum stability/dosage independence. In vivo and ex vivo therapy of severe skin wounds further demonstrated the excellent performance of HPD after loading a therapeutic plasmid. Our work offers a highly efficient, reproducible delivery system for wound gene therapy. It could be extended to other clinical scenarios in which superior gene therapy is urgently demanded.