Synergistic antitumor immune activation in melanoma using LA-PegPI polymeric gene vaccine in conjunction with PD-1 inhibition.

Cancer gene vaccines combined with immune checkpoint inhibitors hold promise for melanoma therapy, but delivery vehicles remain critical. Here, we report LA-PegPI, a galactose-modified polymeric vector that delivers plasmid DNA specifically to dendritic cells (DCs), achieving higher transfection efficiency than commercial reagents with low cytotoxicity. LA-PegPI/pDNA complexes activate TLR4/NF-κB and NLRP3/caspase-1 pathways, inducing DC maturation and secretion of IL-6, TNF-α, IL-1β, and IL-12. In B16-OVA melanoma models, LA-PegPI/pOVA vaccination synergizes with anti-PD-1 to suppress tumor growth, reduce lung metastasis, and prolong survival, accompanied by increased CD8+ T, NK cells, and Th1 cytokines. This polymer platform integrates targeted delivery and intrinsic adjuvanticity, offering a safe strategy to enhance checkpoint immunotherapy.