The urgent need to enhance the early vascularization of dermal substitutes to improve their repair efficiency in skin defect wound presents a significant challenge. This study investigated the impact of dual gene-activated scaffolds (DGAS-M), which combined nanocomposite particles (NPs) encapsulating plasmid DNA (pDNA) of VEGF and aFGF, with the aim of enhancing early vascularization and vascular maturation. In this study, we used the liposomes to encapsulate pDNA and loaded on PLGA knitted mesh-reinforced collagen/chitosan scaffolds (PLGAm/CCS) to prepare DGAS-M. DGAS-M exerted effects on the proliferation of human fibroblasts, angiogenesis, and the synthesis and secretion of growth factors in umbilical vein endothelial cells in vitro. Furthermore, in a rat full-thickness skin defect model, DGAS-M enhanced the survival rate of autologous split-thickness skin grafts during the first 14 days post-surgery. DGAS-M not only accelerated the vascularization process in the wound but also promoted collagen deposition while diminishing the release of inflammatory mediators, ultimately improving the quality of healing. This approach offers a potential solution to address the present clinical problem of skin defect recovery.