Fig. 1
From: Circular RNA vaccine in disease prevention and treatment
The key discoveries and advances in circRNA vaccines. The development of circRNA vaccine can be divided into three stages. Phase 1, natural circRNA is discovered for the first time,43 and the formation mechanism of circRNA is elucidated.47 Phase 2 (1981–2022), the development of in vitro synthesis of circRNA. This phase began in 1981. After that, several key advances are developed, including three synthetic method were developed (enzymatic ligation, 1982;59 PIE system, 1992;60 chemical ligation, 199361), foreign sequences circularization (1994),62 introduction of IRES to engineer translational circRNA (1995),63 engineering translational circRNA via PIE system (1998),64 purification of circRNA by HPLC (2011),65 identification of various IRES candidates (2016),66 efficient optimization of PIE system (2018),35,67 reduction of artificial circRNA immunogenicity (2019) 38,68 and achievement of high translation efficiency (2022).69 Phase 3 (2022~), engineering circRNA vaccines are used for the first time in the treatment and prevention of COVID-19 and melanoma.27,28,29,30,31 Future development will continue to advance
