Abstract

Obesity-linked diabetes, driven by chronic inflammation, ectopic lipid deposition, and multi-organ insulin 
resistance, remains difficult to treat with conventional pharmacotherapy due to poor drug solubility, rapid 
degradation, off-target effects, and suboptimal exposure in key metabolic tissues. Smart nanocarriers engineered 
at the 1–200 nm scale with programmable composition, surface chemistry, and stimuli-responsiveness offer a 
way to concentrate antidiabetic payloads in adipose tissue, liver, skeletal muscle, pancreatic islets, and the gut 
while minimizing systemic toxicity. This review surveys design principles and translational considerations for 
polymeric, lipidic, inorganic, and biomimetic nanocarriers that deliver small molecules, peptides/proteins (e.g., 
insulin, GLP-1 agonists), and nucleic acids (siRNA/ASO/mRNA/CRISPR). We highlight active homing 
strategies (e.g., hepatocyte ASGPR–GalNAc, adipose-vasculature–targeting peptides, β-cell GLP-1R ligands, 
macrophage mannose/CD206), and “smart” release modalities triggered by glucose, pH, redox/ROS, enzymes, 
heat, ultrasound, or magnetic fields. We critically examine oral, transdermal microneedle, and subcutaneous 
depot routes and discuss pharmacokinetics, immunogenicity, scale-up, and regulatory quality attributes. Finally, 
we outline frontier opportunities for organelle-level targeting, multi-omic personalization, and combined 
metabolic–immune modulation together with practical roadblocks such as manufacturing reproducibility, in 
vivo heterogeneity of human adipose depots, and equitable access. Collectively, smart nanocarriers are poised to 
upgrade the therapeutic index of antidiabetic regimens in obesity, provided that material safety, targeting 
specificity, and manufacturability are addressed in human-centric studies.