Extracellular vesicles hybrid plasmid-loaded lipid nanovesicles for synergistic cancer immunotherapy

Combination immunotherapy of cancer vaccines with immune checkpoint inhibitors (ICIs) represents a promising therapeutic strategy for immunosuppressed and cold tumors. However, this strategy still faces challenges, including the limited therapeutic efficacy of cancer vaccines and immune-related adverse events associated with systematic delivery of ICIs. Herein, we demonstrate the antitumor immune response induced by outer membrane vesicle from Akkermansia muciniphila (Akk-OMV), which exhibites a favorable safety profile, highlighting the potential application as a natural and biocompatible self-adjuvanting vesicle. Utilizing tumor cell-derived exosome as an antigen source and Akk-OMV as a natural adjuvant, we construct a cancer vaccine formulation of extracellular vesicles hybrid lipid nanovesicles (Lipo@HEV) for enhanced prophylactic and therapeutic vaccination by promoting dendritic cell (DC) maturation in lymph node and activating cytotoxic T cell (CTL) response. The Lipo@HEV is further loaded with plasmid to enable gene therapy-mediated PD-L1 blockade upon peritumoral injection. Meanwhile, it penetrates into lymph node to initiate DC maturation and CTL activation, synergistically inhibiting the established tumor. The fabrication of extracellular vesicles hybrid plasmid-loaded lipid nanovesicles reveals a promising gene therapy-guided and vesicle-based hybrid system for therapeutic cancer vaccination and synergistic immunotherapy strategy. Schematic illustration of fabricated Lipo-PD-L1@HEV for synergistic cancer immunothearpy. After thin-film hydration of cationic liposome, incubation of cationic liposome with PD-L1 trap plasmid, and purification of tumor cell-derived exosome and Akk-OMV, the Lipo-PD-L1@HEV was fabricated by fusing extracellular vesicles with plasmid-loaded cationic liposome. Upon peritumoral injection, Lipo-PD-L1@HEV can localize in tumor for PD-L1 blockade, and penetrate into lymph node to efficiently initiate DC maturation, antigen presentation and CTL activation, synergistically inhibiting the established tumor. [Display omitted]