Our ultimate research goal is to develop clinically translatable nucleic acid therapeutics and vaccines. In this talk, we will discuss our research in the engineering of circular RNA (circRNA) therapeutics and vaccines, as well as the development of their delivery systems, for versatile application in cancer immunotherapy, prevention of infectious diseases, and gene therapy of genetic diseases. circRNA vaccines are highly stable with sustained production of encoded proteins and peptides, which can be leveraged to promote the prophylactic or therapeutic efficacies while minimizing adverse side effects. Accompanied with circRNA engineering, novel lipid nanoparticles were developed to promote circRNA delivery, for example, to alveoli macrophages for promoting mucosal immunity, and to airway epithelial cells for the gene therapy of cystic fibrosis. Based on these, we will discuss 1) circRNA vaccines that elicit robust and long-lasting CD8+/CD4+ T cell responses for tumor combination immunotherapy; 2) pulmonary delivery of circRNA vaccines that elicit respiratory mucosal immunity for the prevention of viral infection and for the immunotherapy of lung metastatic melanoma; 3) pulmonary delivery of a circRNA encoding a full-length wildtype cystic fibrosis transmembrane conductance regulator (CFTR) protein for the gene therapy of cystic fibrosis; and 4) non-coding circular guide RNA have been developed for ADAR and Cas13d gene editing.