Academic Journal
Hepatocyte-specific partial cellular reprogramming via selective OSK mRNA lipid nanoparticle attenuates liver fibrosis.
| Τίτλος: | Hepatocyte-specific partial cellular reprogramming via selective OSK mRNA lipid nanoparticle attenuates liver fibrosis. |
|---|---|
| Συγγραφείς: | Zhang C; Human Phenome Institute, Fudan University, Shanghai 201203, China., Bai Y; Human Phenome Institute, Fudan University, Shanghai 201203, China., Yin Q; Human Phenome Institute, Fudan University, Shanghai 201203, China., Li J; Human Phenome Institute, Fudan University, Shanghai 201203, China., Huang K; Human Phenome Institute, Fudan University, Shanghai 201203, China., Qiu M; Human Phenome Institute, Fudan University, Shanghai 201203, China; Center for mRNA Translational Research, Fudan University, Shanghai 200438, China; Zhangjiang mRNA Innovation and Translation Center, Shanghai 201203, China. Electronic address: mqiu@fudan.edu.cn. |
| Πηγή: | Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2026 Feb 10; Vol. 390, pp. 114569. Date of Electronic Publication: 2025 Dec 22. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Publishers Country of Publication: Netherlands NLM ID: 8607908 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4995 (Electronic) Linking ISSN: 01683659 NLM ISO Abbreviation: J Control Release Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Amsterdam : Elsevier Science Publishers, 1984- |
| Ιατρικοί όροι (MeSH): | Nanoparticles*/administration & dosage , Nanoparticles*/chemistry , RNA, Messenger*/administration & dosage , Hepatocytes*/metabolism , Liver Cirrhosis*/therapy , Liver Cirrhosis*/genetics , Liver Cirrhosis*/pathology , Octamer Transcription Factor-3*/genetics , Lipids*/chemistry , Lipids*/administration & dosage , SOXB1 Transcription Factors*/genetics , Kruppel-Like Transcription Factors*/genetics , Cellular Reprogramming*, Animals ; Kruppel-Like Factor 4 ; Mice, Inbred C57BL ; Male ; Mice ; Humans ; Liposomes |
| Περίληψη: | Liver fibrosis is a major global health burden with no approved therapies. Transient expression of reprogramming factors Oct4, Sox2, and Klf4 (OSK) promotes tissue regeneration without inducing full pluripotency, which represents an attractive regenerative therapy. Here, we introduce a hepatocyte-specific mRNA delivery strategy for in vivo partial cellular reprogramming using a chemically defined lipid nanoparticle (LNP) platform. We synthesized a series of natural unsaturated fatty alcohol-based ionizable lipids and identified a lead compound, H4T3, with mRNA delivery efficacy comparable to SM102. Further formulation optimization led to a simplified, phospholipid-free, three-component LNP formulation, H4T3_F6 that exhibits high potency and enhanced hepatocyte selectivity, alongside minimal immunogenicity and an overall favorable safety profile. Hepatocyte-specific delivery of OSK mRNA via H4T3_F6 LNPs transiently reprogrammed fibrotic hepatocytes into progenitor-like cells, rejuvenated hepatic gene expression, and promoted functional regeneration. This rejuvenation process downregulates fibrogenic mediators (Tgfb1, Pdgfb), disrupting hepatocyte-stellate cell signaling and halting extracellular matrix (ECM) deposition. The integrated reprogramming and paracrine modulation collectively shift the liver microenvironment from a fibrotic to a regenerative state in a CCl (Copyright © 2025 Elsevier B.V. All rights reserved.) |
| Contributed Indexing: | Keywords: Cellular reprogramming; Hepatocyte-specific OSK mRNA delivery; Lipid nanoparticles; Liver fibrosis; mRNA |
| Substance Nomenclature: | 0 (Kruppel-Like Factor 4) 0 (RNA, Messenger) 0 (Klf4 protein, mouse) 0 (Octamer Transcription Factor-3) 0 (Lipids) 0 (SOXB1 Transcription Factors) 0 (Kruppel-Like Transcription Factors) 0 (Sox2 protein, mouse) 0 (Pou5f1 protein, mouse) 0 (Lipid Nanoparticles) 0 (KLF4 protein, human) 0 (Liposomes) |
| Entry Date(s): | Date Created: 20251224 Date Completed: 20260119 Latest Revision: 20260705 |
| Update Code: | 20260705 |
| DOI: | 10.1016/j.jconrel.2025.114569 |
| PMID: | 41443352 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-4995 |
|---|---|
| DOI: | 10.1016/j.jconrel.2025.114569 |