LPA1 Antagonist-Derived LNPs Deliver A20 Mrna and Promote Anti-Fibrotic Activities

Activated fibroblasts are major mediators of pulmonary fibrosis. Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix (ECM) in the lung interstitial section. Therefore, fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis (IPF). Here, we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1 (LPA1) and the inflammatory pathway through tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) in fibroblasts. First, we synthesized a series of LPA1 antagonists, AM095 and AM966, derived amino lipids (LA lipids) which were formulated into LA-lipid nanoparticles (LA-LNPs) encapsulating mRNA. Specifically, LA5-LNPs, with AM966 head group and biodegradable acetal lipid tails, showed efficient A20 mRNA delivery to lung fibroblasts in vitro (80.2