Citric acid–crosslinked carboxymethyl cellulose hydrogel microneedles enable gentle loading and rapid transdermal delivery of insulin

Transdermal insulin delivery using microneedle (MN) systems provides a promising, patient-friendly alternative to conventional subcutaneous injections. In this study, we developed a citric acid crosslinked carboxymethyl cellulose hydrogel microneedle (CMC-CA HMN) system capable of efficient insulin loading and rapid, pH-triggered release. Thermal esterification produced a CMC-CA hydrogel enriched with abundant carboxyl groups, facilitating electrostatic insulin loading under acidic conditions and immediate release at physiological pH. Fourier transform infrared (FTIR) spectroscopy confirmed successful ester crosslinking. The optimized hydrogel exhibited a high insulin loading capacity (8.7 mg g −1 ) driven primarily by electrostatic interactions. Mechanical tests demonstrated sufficient needle strength for reliable skin penetration, and ex vivo tests on porcine skin verified effective insertion and rapid insulin diffusion into dermal layers. In diabetic rats, a 0.6 IU insulin‑loaded HMN patch yielded glucose‑lowering and pharmacokinetic profiles closely matching those of a 0.2 IU subcutaneous injection, while 0.3 IU produced a smaller effect. Histological analyses further confirmed excellent biocompatibility. The developed CMC-CA HMN platform thus represents a scalable, safe, and efficient strategy for transdermal insulin delivery, substantially advancing the clinical potential of microneedle-mediated protein therapies.