Targeted Therapeutics for Liver Fibrosis

Liver fibrosis arises from chronic injury, leading to excessive deposition of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs) and their transdifferentiated myofibroblast progeny. This maladaptive wound-healing response disrupts normal hepatic architecture, compromises organ function and can progress to cirrhosis or hepatocellular carcinoma. Recent advances have shifted the therapeutic paradigm from broadly acting antifibrotic agents towards precision approaches that localise treatment to key cellular mediators or microenvironmental cues. Strategies include targeted modulation of HSC activation, reprogramming of liver macrophages to a reparative phenotype, selective delivery of gene or RNA cargoes via nanocarriers, and enzymatic degradation of established fibrotic collagen. Combined modalities now aim to deactivate profibrogenic signalling, enhance matrix clearance and restore tissue homeostasis while limiting off-target effects. Beyond small molecules and antibodies, novel delivery platforms exploit receptor-mediated uptake, responsive polymer assemblies and lipid nanoparticles to concentrate therapeutic payloads in the injured liver. These precision therapeutics hold global significance by offering more effective, safer interventions for patients with viral, metabolic or toxic liver diseases and by opening translational paths towards reversing established fibrosis in clinical settings.

Research from Nature Portfolio

Relaxin gene therapy has emerged as a potent means of reversing hepatic stellate cell activation. In a seminal study, plasmid DNA encoding the anti-fibrotic peptide relaxin was packaged into lipid–calcium–phosphate nanoparticles functionalised for tumour and aHSC uptake. Preferential delivery to metastatic lesions and fibrotic niches generated an in situ relaxin depot that deactivated myofibroblasts, remodelled the stromal microenvironment and inhibited collagen accumulation. The approach not only attenuated fibrosis in multiple liver metastasis models but also synergised with immune checkpoint blockade to reinvigorate antitumour immunity. This work highlights the dual benefit of targeted gene delivery in both fibrosis resolution and enhancement of co-administered therapies.

Targeted Therapeutics for Liver Fibrosis publication trend

The graph below shows the total number of articles in targeted therapeutics for liver fibrosis across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatic stellate cell (HSC): A pericyte-like cell in the liver that, upon activation by injury, transforms into a myofibroblast and produces ECM proteins.

Extracellular matrix (ECM): Network of collagen and other proteins providing structural support, whose excessive deposition underlies fibrosis.

Myofibroblast: Contractile, ECM-secreting cell derived from activated HSCs that drives tissue scarring.

Reactive oxygen species (ROS): Chemically reactive molecules produced under stress, exploited here as triggers for controlled drug release.

Lipid nanoparticle: A vesicular carrier composed of lipids, used to encapsulate and deliver nucleic acids or drugs to specific cells.

Polarisation (M1/M2): The functional state of macrophages, with M1 being pro-inflammatory and M2 being reparative.

References

1. Relaxin gene delivery mitigates liver metastasis and synergizes with check point therapy. Nature Communications (2019).
2. An Autologous Macrophage‐Based Phenotypic Transformation‐Collagen Degradation System Treating Advanced Liver Fibrosis. Advanced Science (2023).
3. Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review. Journal of Nanobiotechnology (2023).