Abstract

Obesity-driven type 2 diabetes (T2D) is sustained by chronic, low-grade inflammation that disrupts insulin 
signaling across adipose tissue, liver, skeletal muscle, and vascular beds. Hypertrophic adipocytes and stromal 
immune cells form an inflammatory niche characterized by cytokine secretion, lipotoxic stress, hypoxia, and 
extracellular matrix remodeling. Conventional anti-inflammatory agents can improve insulin sensitivity but are 
limited by off-target toxicities, short half-lives, and inadequate delivery to diseased depots. Nanomedicine offers 
a precision toolkit to overcome these barriers by concentrating therapeutics in inflamed tissues, enabling 
intracellular delivery to key immune populations, coordinating controlled and stimuli-responsive release, and 
coupling therapy with imaging for on-treatment monitoring. This review synthesizes mechanistic 
underpinnings of metabolic inflammation; design principles for adipose- and liver-homing nanoparticles; small
molecule, biologic, and nucleic acid payloads that reprogram innate and adaptive immune tone; and theranostic 
approaches for quantifying target engagement. We discuss safety, manufacturability, and regulatory 
considerations unique to chronic metabolic indications and propose clinical trial frameworks that integrate 
continuous glucose monitoring with inflammatory biomarkers and organ-level imaging. By aligning materials 
science with immunometabolic biology, nanomedicine can convert broad immunosuppression into tissue- and 
pathway-selective modulation, improving insulin sensitivity while minimizing systemic risk.