An endoplasmic reticulum membrane-mimetic GPC3 mRNA nanovaccine for specific immunotherapy of hepatocellular carcinoma.

Dendritic cell-targeting mRNA vaccines exhibit robust antitumor immune activation, however, their therapeutic efficacy remains unsatisfactory due to multiple delivery challenges, including carrier complexity, biomaterial toxicity, nucleic acid instability, and endosomal entrapment, which collectively compromise both safety and treatment outcomes. Here, we report the construction of poly T-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles to condense an HCC-specific GPC3 mRNA with a unique poly(A) tail via hydrogen bonding interactions between A-T base pairs, affording P-(H)-m that further undergoes endoplasmic reticulum membrane camouflage to produce the target biomimetic vaccine, P-(H)-m@EMLN. The endoplasmic reticulum membrane enables P-(H)-m@EMLN with simultaneously enhanced endosomal escape properties and immunogenicity, which leads to a high tumor inhibition ratio (TIR) of 98.8% and long-term immunity activation in a Hepa1-6 tumor-bearing mouse model. Overall, this study reports the mRNA vaccine, P-(H)-m@EMLN via hydrogen bonding interactions between the poly T sequence of polymeric carrier and poly A tail of mRNA for robust immunotherapy of hepatocellular carcinoma.