Abstract

Type 2 diabetes (T2D) is driven by insulin resistance, β-cell dysfunction, and impaired incretin biology. While 
subcutaneous insulin and incretin-based therapies have transformed glycemic care, real-world effectiveness is 
limited by hypoglycemia, gastrointestinal side effects, variable absorption, and adherence barriers related to 
injection burden. Targeted nanocarriers offer a strategy to enhance therapeutic index by improving stability, 
depot residence, and tissue-selective delivery of peptide hormones. Nanoparticles can shield insulin and incretin 
mimetics from enzymatic degradation, traverse mucosal barriers, exploit lymphatic transport, and release cargo 
in response to stimuli such as glucose, pH, enzymes, or redox gradients. Ligand-directed systems further bias 
biodistribution toward hepatocytes, adipose, or muscle to better recapitulate physiologic insulin gradients, while 
depot-forming formulations can provide steady exposure with reduced peak–trough fluctuation. This review 
surveys the biological and biophysical barriers that shape hormone delivery; design rules for lipid, polymer, and 
hybrid nanocarriers; advances in oral, pulmonary, transdermal, and intraperitoneal routes; and smart glucose
responsive platforms enabling closed-loop–like control. We discuss safety, manufacturing, and regulatory 
considerations, and outline clinically pragmatic trial designs that integrate pharmacokinetics with continuous 
glucose monitoring and hypoglycemia endpoints. By aligning material science with endocrine physiology, 
targeted nanocarriers can make insulin and incretin therapy safer, more precise, and easier to live with.