Abstract

Glucose-responsive drug delivery systems aim to emulate pancreatic feedback by sensing hyperglycemia and 
releasing therapeutics proportionally, thereby improving time in range while mitigating hypoglycemia. In 
people with diabetes and coexisting obesity, the value proposition is amplified by altered pharmacokinetics in 
expanded adipose depots, variable subcutaneous perfusion, chronic low-grade inflammation, and behavioral 
burdens associated with frequent injections and complex dosing. Smart nanomaterials like lipid, polymer, 
hydrogel, and hybrid architectures endowed with enzymatic, chemical, or physical glucose-sensing motifs offer 
the spatial and temporal control required for adaptive delivery of insulin and adjunct agents. This review 
synthesizes 
design 
principles 
for 
responsive 
nanoplatforms; 
compares 
enzymatic (glucose 
oxidase/dehydrogenase), boronic acid–diol, and lectin strategies; examines device-route integration via 
microneedles, subcutaneous depots, oral and pulmonary formulations; and discusses peroxide management, 
antifouling strategies, and closed-loop–like kinetics. We evaluate safety, manufacturability, and regulatory 
pathways tailored to chronic metabolic indications and obesity-related physiology, and propose clinical trial 
frameworks that pair continuous glucose monitoring with imaging and mechanistic biomarkers. Finally, we 
highlight human factors such as usability, adherence, equity, and compatibility with incretins and SGLT2 
inhibitors that will determine real-world impact. Smart nanomaterials can decouple efficacy from risk by 
matching dose to demand, offering patient-centered control that complements contemporary pharmacotherapy.