(25c) Engineered mRNA-Lnp Platform Enables Spleen-Targeted CAR-T Cell Engineering In Vivo

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in treating hematologic malignancies and autoimmune diseases. However, conventional CAR-T therapies face critical limitations, including complex ex vivo manufacturing, high costs, and long-term toxicities, driving the need for in vivo CAR-T platforms. To address this, we developed a novel mRNA-LNP system engineered for high-efficiency, T cell-specific delivery of CAR-encoding constructs while minimizing off-target effects.

Conventional LNPs predominantly accumulate in the liver, limiting their ability to effectively target the spleen, where harbors a large population of resident T cells. By rationally redesigning ionizable lipids and optimizing LNP formulations, we developed mRNA-LNPs with enhanced spleen tropism and improved T cell specificity following systemic administration. These optimized particles exhibited a 4-fold increase in splenic accumulation and a 3.5-fold enhancement in mRNA expression within splenic T cells compared to the control group. In comparison with FDA-approved LNP standards, our formulation demonstrated significantly higher T cell transfection efficiency and reduced off-target distribution, showing its potential as a next-generation platform for in vivo CAR-T cell therapies.