A glucose-responsive transdermal insulin delivery patch using PBA-based hydrogel and CAGE

• A non-invasive hydrogel patch featuring phenylboronic acid for glucose-triggered insulin release. • Choline geranate (CAGE) forms reversible skin microchannels to enhance macromolecule transport. • Sustained glycemic control in diabetic rats with minimal hemolysis and skin irritation. • Offers a painless, patient-friendly alternative for Type 1 diabetes management This study presents a glucose-responsive hydrogel patch for transdermal insulin delivery, integrating phenylboronic acid (PBA) chemistry and choline geranate (CAGE) ionic liquid to overcome the limitations of conventional injections. Chitosan oligosaccharide grafted with 3-fluoro-4-carboxyphenylboronic acid (COS-FPBA) formed insulin-loaded microparticles (450 nm, 81.1 % ± 1.28 % encapsulation), which were then embedded in a crosslinked polyethylene glycol/chitosan (CSPVA) hydrogel. The COS-FPBA + INs/CSPVA/CAGE patch exhibited glucose-triggered release, achieving 83.8 % ± 6.9 % cumulative insulin release under high glucose (5 mg/mL) over 12 h. An optimal 4 % CAGE ([Ch][Ger]-ILs (1:2)) enhanced transdermal permeation 2.3-fold relative to controls. In diabetic rat models, the patch induced rapid hypoglycemia (within 2 h) and sustained glucose regulation for 12 h, stabilizing postprandial fluctuations (±15 %). Biocompatibility assays showed minimal hemolysis (<2.5 %), high HaCaT cell viability (>84 %), and negligible skin irritation. This platform integrates (1) PBA-driven glucose sensitivity, (2) CAGE-mediated stratum corneum disruption, and (3) Hydrogel-controlled diffusion, offering a non-invasive alternative for Type 1 Diabetes Mellitus (T1DM). Overall, its non-invasive and glucose-responsive features mimics physiological insulin secretion and enable real-time glycemic control—an advancement over static dosing. Such a pain-free, user-friendly therapy has significant potential for clinical translation.