Circular RNA vaccine induces potent T cell responses

Circular RNAs (circRNAs) are a class of RNAs commonly found across eukaryotes and viruses, characterized by their resistance to exonuclease-mediated degradation. Their superior stability compared to linear RNAs, combined with previous work showing that engineered circRNAs serve as efficient protein translation templates, make circRNA a promising candidate for RNA medicine. Here, we systematically examine the adjuvant activity, route of administration, and antigen-specific immunity of circRNA vaccination in mice. Potent circRNA adjuvant activity is associated with RNA uptake and activation of myeloid cells in the draining lymph nodes and transient cytokine release. Immunization of mice with engineered circRNA encoding a protein antigen delivered by a charge-altering releasable transporter induced innate activation of dendritic cells, robust antigen-specific CD8 T cell responses in lymph nodes and tissues, and strong antitumor efficacy as a therapeutic cancer vaccine. These results highlight the potential utility of circRNA vaccines for stimulating potent innate and T cell responses in tissues.SignificanceCircular RNAs (circRNAs) are a unique class of RNAs that are highly stable compared to linear mRNAs and can be engineered to provide durable protein expression. This study demonstrates that circRNA encoding antigenic protein sequences delivered by a charge-altering releasable transporter can effectively serve as both an adjuvant and an immunogen, inducing potent cellular immunity and leading to tumor clearance when used as a therapeutic vaccine. These results suggest engineered circRNAs for the development of vaccines and therapeutics.

Automated summary

Circular RNAs (circRNAs) are highly stable RNAs that can be engineered to provide durable protein expression. This study shows that circRNA encoding antigenic protein sequences delivered by a charge-altering releasable transporter can serve as both an adjuvant and an immunogen, inducing potent cellular immunity and leading to tumor clearance as a therapeutic vaccine. These results suggest the potential utility of engineered circRNAs for the development of vaccines and therapeutics.