Endogenous Corticosteroid Derived Lipid Nanoparticles (Cortico LNPs) Enable Selective mRNA Delivery to the Spleen

Abstract Lipid nanoparticles (LNPs) have emerged as effective delivery vehicles for nucleic acids. However, conventional LNP formulations face several limitations, including poor endosomal escape and ApoE‐mediated liver tropism. Here, a novel class of LNPs, endogenous corticosteroid‐derived LNPs (cortico LNPs), is introduced in which the cholesterol component is replaced with endogenous corticosteroids, resulting in redirection from the liver to the spleen. Multiple corticosteroids and their precursors, including corticosterone, 11‐deoxycortisol, 11‐deoxycorticosterone, progesterone, 11β‐hydroxyprogesterone, and pregnenolone, are investigated due to their critical roles in immune regulation, stress response, and metabolism. Among these, corticosterone‐ and progesterone‐LNPs demonstrate robust protein expression in vivo with remarkable spleen selectivity of 97% and 99%, respectively. Additionally, these LNPs display superior safety profiles compared to the clinical SM‐102 formulation. It is proposed that the adsorption of β2‐glycoprotein I (β2‐GPI) on the LNP surface mediates the spleen‐specific delivery. Notably, this approach is also compatible with other clinically approved ionizable lipids, such as MC3 and ALC‐0315, underscoring the versatility of corticosteroid modifications in optimizing organ tropism across different LNP platforms. These findings highlight the therapeutic potential of cortico LNPs to reprogram organ distribution and enhance gene targeting beyond the liver, representing an exciting advancement in the development of precision immunotherapy and gene therapy.