Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by steatosis, inflammation, and progressive fibrosis. Increasing evidence suggests that cellular senescence contributes to MASH progression by promoting lipid accumulation, inflammatory signaling, and fibrogenic responses, highlighting hepatic senescent cells as a potential therapeutic target. Senolytics selectively eliminate senescent cells, but their application in MASH remains insufficiently explored. In this study, we developed in vitro models integrating hepatic lipid accumulation and hepatocyte-macrophage inflammatory crosstalk to facilitate investigation of the contribution of cellular senescence to MASH pathology and to evaluate senescence-targeted interventions. Senescent hepatic cells showed enhanced lipid accumulation and amplified inflammatory signaling with macrophages. Natural Extracellular Vesicles (EVs) derived from adipocytes reduced senescence-associated phenotypes but exhibited context-dependent biological effects, highlighting the limited control over their intrinsic bioactivity. Navitoclax, a senolytic targeting anti-apoptotic BCL-2 family proteins, reduced senescence-associated phenotypes, but its clinical use is limited by its dose-dependent toxicity. Hence, we conceived nano-Cell Vesicle Technology Systems (nCVTs), a biohybrid-based platform combining cell-derived membranes with synthetic lipids for controlled delivery of navitoclax. Navitoclax-loaded nCVTs retained senolytic activity and reduced inflammatory signaling and fibrotic activation in vitro. Importantly, in a Western diet- and fructose-induced (WDF) MASH mouse model, navitoclax-loaded AML-12-derived nCVTs alleviated hepatic lipid accumulation while reducing histopathological activity score and fibrotic profiles. Neither navitoclax formulation reduced platelet counts or hemoglobin concentrations at the tested dose. Collectively, these findings support cellular senescence as a therapeutically relevant target for MASH and identify nCVTs as a promising engineered platform for controlled senolytic delivery.
