Nanomedicine-based targeted strategies for metabolic dysfunction-associated steatotic liver disease: Unraveling pathogenic crosstalk and overcoming clinical barriers

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting approximately one-third of the global adult population, acting as the primary driver of cirrhosis and hepatocellular carcinoma. Despite its growing incidence and substantial clinical and socioeconomic toll, clinical treatment of MASLD remains severely limited by the absence of U.S. Food and Drug Administration (FDA)-approved pharmacotherapies, suboptimal hepatic targeting of existing agents, off-target adverse effects, and limited infiltration into the fibrotic hepatic microenvironment. Nanomedicine has emerged as a promising strategy to address these limitations and advance precision treatment for chronic liver diseases, yet a systematic review unifying the multifactorial pathogenesis of MASLD, rational target selection, and advanced nanoplatform development remains lacking. Herein, we systematically elaborate the multi-hit pathogenic cascade of MASLD, covering metabolic imbalance, oxidative and inflammatory injury, aberrant programmed cell death, inter-organ signaling crosstalk, and fibrogenic transformation, with a focus on recently identified mechanisms, including single-cell transcriptomic heterogeneity and epigenetic regulation. We further clinically translatable therapeutic targets, and comprehensively summarize the rational design, structure-activity relationships, hepatic targeted delivery strategies, therapeutic outcomes, and underlying molecular mechanisms of state-of-the-art nanosystems. Moreover, we evaluate preclinical achievements and dissect core translational obstacles and highlight future frontiers, including artificial intelligence-assisted nanodesign, theranostic integration, and oral liver-targeted nanosystems.