Abstract

The inefficient delivery of lipid nanoparticles (LNPs)-encapsulated mRNA to activated fibroblasts in fibrotic tissues remains a major challenge for antifibrotic therapy. To overcome this, we develop a fibrosis organ and cell unified-targeting system (FOCUS) for mRNA delivery with LNPs. FOCUS LNPs combines an ionizable lipid library (synthesized via Ugi multicomponent reactions) with fibroblast activation protein-α (FAP)-targeting lipid-like ligands. These LNPs achieve ∼3-fold and ∼12-fold greater mRNA expression in fibrotic liver and lung, along with ∼2–5-fold higher fibroblast distribution─unattainable by organ- or ligand-only targeting. As proof of concept, Pentraxin-2 mRNA (mPTX-2)-loaded FOCUS LNPs drive localized PTX-2 production in murine models of pulmonary and hepatic fibrosis, reducing collagen deposition by 60–80% while avoiding systemic side effects like impaired wound healing. Mechanistically, mPTX-2 FOCUS LNPs suppress monocyte-to-fibrocyte differentiation, M2 macrophage polarization, and fibroblast activation. This work establishes a precision mRNA delivery platform for fibrotic diseases, offering a safer and more effective therapeutic strategy.