FAP-Synergistic Organ-Targeted mRNA-LNP for Overcoming Delivery Barriers in Hepatic and Pulmonary Fibrosis

  • J Am Chem Soc. 2026 Mar 11;148(9):9309-9327. doi: 10.1021/jacs.5c16886.
Chenlong Wei  1  2 ,  Xinzhu Shan  1  2 ,  Yuxuan Huang  1  2 ,  Bin Ma  1  2 ,  Zhiqiang Zhao  1  2  3 ,  Yian Fang  1  2 ,  Chengrui Bai  1  2 ,  Zihan Zhang  1  2 ,  Peng Zhao  1  2 ,  Huijuan Zhang  1  2 ,  Yu Hou  1  2 ,  Tianjiao Ji  4 ,  Zhongtang Li  1 ,  Song Song  1 ,  Fei Xie  5 ,  Lei Miao  1  2  6
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 2. Beijing Key Laboratory of Advanced Pharmaceutical Preparation, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 3. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing 100190, China.
  • 5. Joint Research Institute of Medical and Pharmaceutical Sciences, Clinical Trials Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 6. Peking University-Yunnan Baiyao International Medical Research Center, Beijing 100191, China.
PMID: 41731656 DOI: 10.1021/jacs.5c16886
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.

Products