CS22021 is a novel, synthetically engineered ionizable sterol lipid (ISL) developed by CanSino, specifically designed for advanced mRNA delivery via lipid nanoparticles (LNPs). Its core innovation lies in its unique molecular architecture, which integrates a cholesterol moiety directly conjugated to a branched aliphatic tail (derived from ALC-0315) and a hydrophilic headgroup containing tertiary amines. This bifunctional design allows CS22021 to simultaneously fulfill the roles of both the ionizable lipid (for mRNA binding/encapsulation and endosomal escape) and the structural cholesterol component within LNPs. Consequently, CS22021 enables the formulation of highly efficient three-component LNPs (ISL-3C-LNPs), eliminating the need for free cholesterol, using only itself, the phospholipid DOPE (crucial for forming stable, uniform nanoparticles without defects), and a PEGylated lipid. When formulated into LNPs and administered intramuscularly, CS22021 demonstrates a critical property: it achieves localized mRNA expression predominantly at the injection site, significantly minimizing off-target delivery (especially to the liver/spleen) and associated systemic toxicity. Furthermore, mRNA vaccines delivered by CS22021-based LNPs elicit robust and balanced immune responses, including strong antigen-specific IgG antibodies and, notably, a significantly enhanced CD8+ T cell response compared to conventional four-component LNPs. This combination of efficient mRNA encapsulation/delivery, localized expression for improved safety, and potent induction of cellular immunity, particularly CD8+ T cells, positions CS22021 as a highly promising lipid platform, especially for next-generation mRNA vaccine applications like cancer immunotherapy.
