Dual-responsive PEG-lipid polyester nanoparticles for siRNA and vaccine delivery elicits anti-cancer immune responses by modulating tumor microenvironment

Cancer vaccine-based immunotherapy has great potential; however, vaccine has been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NP) for tumor-targeted delivery were proposed. PEG BR647-NP containing model tumor associated antigen (TAA) OVA and signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to tumor. PEG BR647-NP was internalized by tumor associated dendritic cells (TADCs), where TAA and siRNA were released into cytoplasm via endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, the released STAT3 siRNA acted to relieve TADCs dysfunction, promote TADCs maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, PEG BR647-NP was ingested by tumor cells, and could kill tumor cells by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NP could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADCs dysfunction, promoted TADCs maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect can boost the vaccination for tumor immunotherapy. Thus, PEG BR647-NP efficiently delivered vaccine and STAT3 siRNA to tumor, and modulated immunosuppressive TME, provided better antitumor effects.