Carbon dot-lipidoid nanocarriers for superiorly biocompatible nasal mRNA cancer vaccination

In this study, we synthesized an ionizable lipidoid, Cdoids, composed of carbon dots (Cdots) conjugated with oleic acid that exhibits superior biocompatibility compared to conventional ionizable lipids while retaining intrinsic fluorescence for real-time tracking and optimal nasal delivery of mRNA cancer vaccines. These properties make Cdoids a promising candidate for lipid nanoparticle (LNP) formulations. Incorporating Cdoids into LNPs enhances mRNA delivery efficiency via intranasal (IN) administration, providing a viable alternative to intramuscular (IM) injection. The unique structural features of Cdoids facilitate the formation of stable nanoparticles that efficiently encapsulate and deliver mRNA leveraging the immunological environment of the nasal mucosa to induce robust systemic and localized immune responses. Notably, Cdoids broaden the range of endocytosis mechanisms beyond conventional LNPs, leading to significantly enhanced mRNA expression within target cells. Comparative analyses demonstrated that Cdoids surpass commercially available ionizable lipids, such as SM-102, in both mRNA delivery efficiency and safety, exhibiting lower cytotoxicity in vitro and improved mRNA expression in vivo following IN administration. Furthermore, when applied as an mRNA cancer vaccine platform, Cdoids-based LNPs elicited strong antigen-specific immune responses, leading to effective tumor growth suppression. This study highlights the potential of Cdoids as an advanced ionizable lipid for LNP-based mRNA therapeutics and introduces an innovative strategy for optimizing intranasal vaccine delivery.