mRNA compartmentalization via multimodule DNA nanostructure assembly augments the immunogenicity and efficacy of cancer mRNA vaccine | Science Advances

Messenger RNA (mRNA) vaccine has fueled a great hope for cancer immunotherapy. However, low immunogenicity, caused by inefficient mRNA expression and weak immune stimulation, hampers the efficacy of mRNA vaccines. Here, we present an mRNA compartmentalization–based cancer vaccine, comprising a multimodule DNA nanostructure (MMDNS)–assembled compartment for efficient mRNA translation via in situ localizing mRNA concentration and relevant reaction molecules. The MMDNS is constructed via programmable DNA hybridization chain reaction (HCR)–based strategy, with integrating antigen-coded mRNA, CpG oligodeoxynucleotides (ODNs), acidic-responsive DNA sequence, and dendritic cells targeting aptamer. MMDNS undergoes in situ assembly in acidic lysosomes to form a micro-sized aggregate, inducing an enhanced CpG ODN adjuvant efficacy. Subsequently, the aggregates escape into cytoplasm, providing a moderate compartment which supports the efficient translation of spatially proximal mRNA transcripts via localizing relevant reaction molecules. The mRNA compartmentalization–based vaccine boosts a strong immune response and effectively inhibits tumor growth and metastasis, offering a robust strategy for cancer immunotherapy.