A Pathophysiology-Informed, Negentropy-Oriented Strategy for Nanomedicine in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic liver disorder driven by an ensemble of interrelated pathological processes, including insulin resistance, lipid accumulation, oxidative stress, immune dysregulation, gut microbiota imbalance, and hepatocyte injury-induced cell death. These overlapping mechanisms pose significant challenges for effective treatment, as conventional single-target therapies often fail to address the systemic complexity of the disease. Recent advances in functional nanomedicine have introduced promising avenues for MASLD intervention by enabling the development of nanoplatforms specifically engineered to interact with disease-specific pathophysiological features. These systems incorporate stimuli-responsive drug release, targeted hepatic accumulation, and intrinsic therapeutic activity, allowing for simultaneous modulation of multiple pathological pathways. This review presents a pathophysiology-informed framework for nanomedicine design in MASLD therapy. How diverse platforms are strategically tailored to regulate reactive oxygen species (ROS) production, modulate immune imbalance, restore insulin signaling, inhibit ferroptosis, and rebalance gut microbial dysbiosis is examined. Moreover, emerging approaches such as carrier-free, self-assembling systems and multifunctional yet intentionally minimalist architectures that enhance translational potential are highlighted. Together, these strategies exemplify a shift toward mechanism-driven, entropy-informed nanotherapeutics, wherein negentropy-oriented and leading-axis design principles offer a promising roadmap for restoring metabolic homeostasis in complex disease contexts such as MASLD.