Abstract

Invasive Aspergillus fumigatus infection poses a serious threat to immunocompromised individuals, characterized by high morbidity and mortality. Given the challenges of time-consuming diagnosis, limited therapeutic options, and the increasing emergence of drug resistance, there is an urgent need to develop novel and effective preventive strategies. Circular RNA (CircRNA) vaccines represent an emerging vaccine platform that exhibits high stability in vivo , enables sustained antigen expression, and can elicit robust and durable immune responses. Consequently, they hold considerable potential for the prevention of infectious diseases. In this study, we designed and constructed two circRNA vaccines, each encoding a fusion antigen derived from non-transmembrane regions of the iron ion permease FtrA located in the cell membrane of A. fumigatus . The circRNA vaccines were prepared using a group I intron-based cis -acting ribozyme system (CARS) and delivered via lipid nanoparticles (LNPs) in a murine model. The results revealed that the circRNA FtrA2 vaccine could effectively induce both cellular and humoral immune responses. Following challenge with A. fumigatus , vaccinated mice, particularly those receiving circRNA FtrA2 , exhibited a significant reduction in fungal burden in the lungs compared with the unvaccinated controls. Furthermore, lung pathology was markedly alleviated, and survival rate was notably improved. Collectively, these findings highlight a promising and innovative vaccine for combating invasive A. fumigatus infection.