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

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.