Ionizable Lipid‐Dependent Optimization of Steroid Lipid Nanoparticles With Tunable Immunomodulatory Properties

Abstract

ABSTRACT Lipid nanoparticles (LNPs) are a leading platform for nucleic acid delivery, yet their intrinsic adjuvanticity poses a significant materials design challenge for applications requiring immunological quiescence. Here, we report a modular engineering strategy that incorporates FDA‐approved corticosteroids into LNP formulations, creating a new class of steroid LNPs with tunable anti‐inflammatory properties. Through systematic screening of steroid and cholesterol substitution ratios, we establish structure–property relationships governing mRNA encapsulation efficiency, physicochemical characteristics, and inflammation suppression. Triamcinolone (TRI) emerges as our lead steroid, with 50% cholesterol substitution in SM‐102 LNPs preserving physicochemical characteristics. Importantly, we show that optimal substitution ratios are ionizable lipid‐dependent—80% for MC3 and 50% for SM‐102 and ALC‐0315—revealing fundamental design principles for these dual‐functional LNPs. In an endotoxemia mouse model, TRI LNPs administered intramuscularly maintain mRNA delivery efficacy while reducing inflammatory cytokines by ∼4‐fold compared to SM‐102 LNPs. In a multiple sclerosis mouse model, TRI LNPs delivering therapeutic mRNA promote antigen‐specific tolerance in spinal cord tissue and protect against paralysis. Compared to SM‐102 LNPs, TRI LNPs reduce inflammatory cytokines by ∼3‐fold and prolong protection against paralysis. Together, our work introduces a generalizable materials design strategy for engineering LNPs with tunable immunomodulatory properties to expand their therapeutic utility.