PROF. GUIZHUI ZHU

Vaccines have significantly improved the prophylaxis and treatment outcomes of diseases, including many types of infectious diseases and cancer. Antigen-encoding messenger RNA (mRNA) vaccines are an emerging class of vaccines featured with low safety concerns over some other vaccine forms associated with genomic integration, viral infection, preexisting anti-viral-vector immunity, and resistance to degradability. However, the current technology of mRNA therapeutics and vaccines relies on long mRNA that is limited by complicated and often inefficient enzymatic manufacturing, stringent transportation and storage conditions, as well as limited biostability that reduces antigen production efficiency and immunomodulation efficacy. Here, we will discuss our recent development of small circular mRNA (circRNA) as a novel class of mRNA vaccines. The small circRNA has several notable features: 1) in contrast to conventional long mRNA, circRNA can leverage existing RNA manufacturing facilities, automated chemical synthesis technology, versatile RNA chemical modifications, and advanced RNA delivery systems such as liposome; 2) the lack of termini in circRNA prevents exonuclease degradation and extends their lifespans relative to linear RNA; 3) circRNA is self-adjuvanted for immunostimulation without additional immunostimulant adjuvants; and 4) circRNA produces multivalent and/or long peptide antigens, which, relative to monovalent or minimal antigen epitopes, promote intracellular antigen processing and presentation while minimizing immune tolerance. Nanoparticles promoted the delivery of sci-mRNA to immune tissues and cells. As a result, circRNA elicited potent innate and adaptive immune responses with immune memory in mice, which enabled mice to resist the challenge of antigen-expressing cells and inhibited the progression of established tumors for immunotherapy. Taken together, these results make circRNA a promising novel platform of RNA vaccines.