Nanotherapeutic Strategies for MASLD: From Pathological Mechanisms to Targeted Delivery Systems

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive metabolic liver disorder driven by hepatic lipid overload, oxidative stress, mitochondrial dysfunction, innate immune activation, insulin resistance, gut–liver axis dysregulation, and liver fibrosis. These interconnected pathological processes involve hepatocyte injury, macrophage-mediated inflammation, liver sinusoidal endothelial cell dysfunction, hepatic stellate cell activation, and extracellular matrix deposition. However, conventional therapeutic agents are often limited by poor solubility, insufficient stability, low intrahepatic exposure, nonspecific distribution, and inadequate target-cell selectivity. Nanoparticle-based delivery systems may overcome these limitations by improving drug stability, hepatic accumulation, controlled release, and cell-specific delivery. This review summarizes recent advances in nanotherapeutic strategies for MASLD from three complementary perspectives: intervention in key pathological processes, cell-specific delivery to major hepatic cell populations, and the design characteristics of different nanoplatforms. We discuss nanodelivery strategies targeting lipid metabolic dysfunction, oxidative injury, inflammation, insulin resistance, gut–liver axis dysfunction, and fibrogenesis, as well as delivery approaches directed at hepatocytes, hepatic stellate cells, liver macrophages, and liver sinusoidal endothelial cells. Multicellular co-delivery strategies for modulating pathological crosstalk are also considered. In addition, we compare the advantages and limitations of inorganic nanoparticles, polymeric nanoparticles, liposomes and other lipid-based nanosystems, and bio-derived or biomimetic nanocarriers. Particular attention is given to how carrier composition, physicochemical properties, surface functionalization, and release behavior can be matched with therapeutic cargoes, target cells, and pathological processes. Although these platforms provide opportunities for multi-process and cell-specific intervention in MASLD, most evidence remains preclinical. Major barriers to clinical translation include long-term safety, controllable biodistribution, differences between experimental models and human disease, scalable manufacturing, batch-to-batch consistency, and standardized quality evaluation. Addressing these issues during nanoplatform design and assessment will be essential for translating targeted nanodelivery systems into clinically applicable therapies for MASLD. Keywords: metabolic dysfunction-associated steatotic liver disease, nanomedicine, lipid metabolism, oxidative stress, hepatic fibrosis, gut–liver axis