Obesity represents a global health crisis characterized by chronic adipose tissue (AT) inflammation (metaflammation) driven by pro-inflammatory M1 macrophage (MΦ) polarization, adipocyte hypertrophy, and impaired thermogenic capacity of white adipose tissue (WAT). While interleukin-4 (IL-4) potently induces M2 MΦ polarization, its clinical translation is limited by poor stability, rapid clearance, and off-target effects. Here, we engineered lipid nanoparticles (IL-4/LNP) via simple, robust thin-film hydration and extrusion to enable sustained IL-4 delivery to MΦs in inflamed AT. In vitro, IL-4/LNP achieved >70% encapsulation efficiency, a uniform ∼150 nm size, and superior M1 to M2 MΦ reprogramming compared with free IL-4, as evidenced by CD206 upregulation, reduced CD80/CD40 expression, and attenuated TNF-α/IL-6 secretion in LPS-stimulated MΦ. In adipocyte-mimicking cells (3T3-L1)-MΦ co-cultures representing white and brown adipose tissue (BAT), paracrine signaling from IL-4/LNP-polarized M2 MΦs drove a profound reduction in lipid droplets (LDs) and beiging, with decreased Feret diameter and integrated optical density. Using a high-fat diet-induced obese mouse model, localized inguinal/visceral AT injections blunted weight gain by ∼10%, induced multilocular beige-like adipocytes across depots, upregulated thermogenic genes (Ucp1 and Pgc1α), downregulated inflammatory markers (IL-6), and improved hepatic steatosis without systemic toxicity. These findings establish IL-4/LNP as a safe, multifunctional platform that links MΦ immunomodulation and adipose browning in obesity therapy. STATEMENT OF SIGNIFICANCE: This study establishes IL-4-loaded lipid nanoparticles (IL-4/LNPs) as a nanomedicine platform that targets the immunometabolic roots of obesity by reprogramming adipose tissue macrophages and promoting white fat browning. IL-4/LNPs are produced by a simple, scalable thin-film hydration-extrusion method, yielding ∼150 nm particles with ∼73% encapsulation, suitable for local adipose delivery. In vitro, the NPs outperform free IL-4 by enhancing M2 polarization, driving paracrine adipocyte remodeling, and reducing lipid burden in 3T3-L1 co-cultures. In high-fat diet-obese mice, depot-specific IL-4/LNP injections limit weight gain, induce adipocyte beiging, improve hepatic steatosis, and reduce systemic inflammation without detectable toxicity, supporting IL-4/LNPs as a translatable cytokine nanotherapy for metaflammatory obesity.
