Cyclen-based lipidoids for mRNA delivery and immunotherapy

As mRNA vaccines continue to gain widespread attention, the development of lipid nanoparticles (LNPs), as the preferred platform for mRNA delivery, has become a key focus of research. 1,4,7,10-Tetraazacyclododecane (cyclen), with its excellent protonation capability and ease of modification, has emerged as a promising candidate for the ionizable head group of lipid materials. In this study, a series of cyclen-based lipidoids with different linkages and hydrophobic tails was designed and conveniently synthesized. Structure-activity relationship studies were performed to screen out the carriers capable of efficient mRNA delivery and with potential for tumor therapeutic applications. <i>In vivo</i> biodistribution experiments in mice revealed that the lipidoid OEs-K, containing both hydroxyl and ester groups in its linkage, exhibited high mRNA delivery efficiency and lymph node-targeting properties. Using a subcutaneous EG.7-OVA tumor model in mice, the delivery of tumor antigen OVA mRNA using the lipidoid material was evaluated for its antitumor immunotherapeutic potential. Results demonstrated that LNPs formulated with OEs-K promoted dendritic cell uptake in lymph nodes, effectively activated immune responses, and inhibited tumor growth. Hematological and histopathological evaluations indicated no significant toxicity to the body. This study provides insights into the design and development of carrier materials for mRNA vaccines.