Enhancing insulin sensitivity by reducing adipocyte senescence using uPAR-targeted nanoparticles in high-fat-diet-induced obese mice.

Abstract

The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-anchored membrane protein that regulates fibrinolysis, cell adhesion, migration, and intracellular signaling. Elevated uPAR expression is linked to numerous pathological conditions, including cancer, inflammation, and metabolic dysfunction. In obesity and aging, increased uPAR levels are associated with chronic inflammation, adipose tissue impairment, and systemic metabolic disturbances. uPAR also modulates adipocyte differentiation and contributes to the progression of inflammatory obesity, while serving as a key regulator of cellular senescence triggered by oncogenic stress, chemotherapy, or aging. These characteristics position uPAR as a compelling therapeutic target for metabolic and age-related diseases. To address this, we developed a nanoparticle-based targeted therapy optimized for senolytic delivery, which enhances accumulation in uPAR-overexpressing cells and improves drug stability. Dasatinib and quercetin, two established senolytic agents, were co-encapsulated into uPAR-targeted hybrid nanoparticles to selectively eliminate senescent cells, reduce inflammation, and restore metabolic homeostasis, presenting a promising therapeutic strategy for obesity- and aging-associated disorders.