How has the inclusion of unconventional lipids improved LNP-mediated mRNA delivery?

Lipid nanoparticles (LNPs) have become the leading platform for mRNA delivery, exemplified by the success of mRNA vaccines. However, LNPs composed of classical lipid materials are still constrained by intrinsic hepatotropism and suboptimal intracellular delivery, restricting their broader clinical utility. To overcome these challenges, researchers are developing unconventional lipids, a class of next-generation lipid materials that are rationally engineered to enhance endosomal escape, confer programmable tissue selectivity, and reduce immunogenicity. In this Special Report, we highlight representative classes of unconventional lipids and discuss their impacts on in vivo mRNA delivery performance. Collectively, these next-generation materials are redefining LNPs from passive carriers into regulatable delivery systems capable of improving delivery efficiency, modulating biodistribution, and enhancing safety profiles. Such innovations are poised to expand the therapeutic reach of mRNA medicines across a wide range of diseases. [PubMed and Web of Science databases were searched for relevant articles published from January 2010 to December 2025].