Hepatocyte-specific partial cellular reprogramming via selective OSK mRNA lipid nanoparticle attenuates liver fibrosis

Dec 24, 2025Journal of controlled release : official journal of the Controlled Release Society

Partial reprogramming of liver cells using targeted OSK mRNA nanoparticles reduces liver scarring

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

H4T3_F6 lipid nanoparticles enable hepatocyte-specific delivery of mRNA that partially reprograms fibrotic liver cells.

Transient expression of reprogramming factors Oct4, Sox2, and Klf4 promotes regeneration without full pluripotency.
The lead compound H4T3 demonstrates mRNA delivery efficacy comparable to existing methods.
A simplified lipid nanoparticle formulation enhances hepatocyte selectivity and reduces immunogenicity.
Reprogrammed fibrotic hepatocytes exhibit rejuvenated gene expression and promote functional regeneration.
Downregulation of fibrogenic mediators disrupts signaling between hepatocytes and stellate cells, halting extracellular matrix deposition.
The overall liver microenvironment shifts from fibrotic to regenerative in a mouse model of liver fibrosis.

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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-induced liver fibrosis mouse model. This study provides proof-of-concept for rejuvenating fibrotic livers via selective mRNA-based in vivo cellular reprogramming, offering a promising strategy for liver fibrosis or age-related tissue repair. 4

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Hepatocyte-specific partial cellular reprogramming via selective OSK mRNA lipid nanoparticle attenuates liver fibrosis

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