Recent Advances in Nanodelivery Systems for Polyphenols in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): An update

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the most prevalent chronic liver disorder worldwide, closely linked to obesity, insulin resistance, and type 2 diabetes mellitus. Despite its rising global burden, there are currently no approved pharmacological therapies targeting MASLD pathogenesis directly. Polyphenolic compounds have demonstrated promising hepatoprotective, antioxidant, and anti-inflammatory properties in preclinical models; however, their poor stability, limited solubility, and low bioavailability hinder clinical translation. This review summarizes the latest advances in nano-drug delivery systems (NDDSs) designed to enhance the therapeutic potential of polyphenols in MASLD. Various nanocarrier platforms, including inorganic, lipid-based, polymeric, and hybrid nanosystems, are discussed with emphasis on their mechanisms of action, pharmacokinetic advantages, hepatocyte-targeting strategies, and translational challenges. Emerging NDDSs markedly enhance polyphenol pharmacodynamics through enhanced intestinal absorption, controlled release, and targeted hepatic accumulation. Lipid-based carriers (liposomes, solid lipid nanoparticles, nanoemulsions, and nanostructured lipid carriers) demonstrate excellent oral bioavailability and safety, whereas polymeric and inorganic systems offer multifunctional therapeutic synergy by modulating oxidative stress, lipid metabolism, and inflammatory pathways. Recent clinical evidence, including nano-micellar curcumin formulations, suggests translational feasibility and safety in MASLD patients. Nevertheless, long-term biosafety, scalability, and interindividual variability remain key challenges for clinical application. Therefore, polyphenols loaded with nanocarrier systems offer a multifaceted therapeutic approach to address the complex metabolic, inflammatory, and fibrotic processes underlying MASLD. Future research should prioritize clinical validation, mechanistic standardization, and regulatory alignment to enable the transition from preclinical innovation to precision nanomedicine in metabolic liver diseases.