Current mRNA vaccines are still limited by product heterogeneity and suboptimal stability that demands extensive modifications with suboptimal immunomodulatory efficacies. Here, we report chemically-defined, highly stable modification-free small circular mRNA (circRNA) vaccines. circRNA showed excellent thermal stability (>6 months) and biostability (>1 week). circRNA vaccine was synchronically self-adjuvanted (by activating pattern recognition receptors) and sustainably produced concatemeric antigens (via rolling circle translation) for efficient and long-lasting antigen presentation. Small circRNA was efficiently loaded in nanocarriers and delivered to lymph node antigen-presenting cells to elicit potent and durable CD8+/CD4+ T cell responses against tumor/oncoviral/viral antigens, in young mice and immunosenescent aged mice. Low-dose (1-10 μg) circRNA elicited 60% antigen-specific T cells, an order of magnitude increase relative to several state-of-the-art modified mRNAs, with less immunotoxicity. Low-dose circRNA vaccines, together with immune checkpoint inhibitors, reduced tumor immunosuppression for robust immunotherapy in multiple tumor models. Moreover, low-dose pulmonary circRNA vaccines protected mice from influenza challenge. Therefore, small circRNA vaccines are promising for various disease prophylaxis and therapy.
Learning Objectives:
Upon completion, participants will be able to understand the structure, preparation, and nanoformulation of small circRNA vaccines.
Upon completion, participants will be able to learn the mechanism of small circRNA vaccines eliciting innate and adaptive immune responses.
Upon completion, participants will be able to obtain knowledge on the unique properties and potential advantages of small circRNA vaccines over state-of-the-art modified linear mRNA vaccines.
Upon completion, participants will be able to learn the cutting-edge development of small circRNA vaccines for cancer combination immunotherapy as well as infectious disease prevention.
