Cutting-edge biotherapeutics and advanced delivery strategies for the treatment of metabolic dysfunction-associated steatotic liver disease spectrum

Feb 9, 2025Journal of controlled release : official journal of the Controlled Release Society

New biological treatments and delivery methods for fatty liver disease linked to metabolism problems

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome.

MASLD may progress to liver cirrhosis or hepatocellular carcinoma.
Existing therapies such as thyroid hormone receptor-β agonists and PPAR agonists show limited effectiveness against the complex pathways driving MASLD.
Recent advancements in targeted therapeutics include RNA interference, mRNA-based gene therapies, and monoclonal antibodies.
Innovative drug delivery systems are being researched to improve the stability and precision of these biotherapeutics.
These delivery strategies aim to enhance target-specific action and reduce systemic exposure, addressing limitations of current treatments.

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Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.

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Cutting-edge biotherapeutics and advanced delivery strategies for the treatment of metabolic dysfunction-associated steatotic liver disease spectrum

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