Current Strategies and Challenges in Stimuli‐Responsive Nanocarriers for Insulin Delivery

A significant challenge in diabetes management is the establishment of self-regulating insulin delivery systems capable of adjusting insulin release in response to variations in blood glucose levels, identical to artificial pancreases. Owing to the adverse conditions of the gastrointestinal tract, insulin and other macromolecular diabetic treatments are administered subcutaneously, which may cause discomfort and inconvenience, resulting in poor patient adherence. Although these systems are classified as closed-loop, they remain a burden and impose responsibility on the individual receiving treatment. To minimize patient burden, glucose-responsive insulin administration methods have been designed. Encapsulating insulin in microgels, nanoparticles, hydrogels, or membranes allows for on-demand release of therapeutic protein by responding to glucose levels through swelling, shrinking, or degradation. Insulin is usually embedded in a matrix with glucose-responsive components that change structure and disintegrate in response to glucose levels. This review focuses on the current challenges faced in the regulated dosage of insulin, covering the most commonly used glucose-responsive systems, including phenylboronic acid, glucose oxidase, and glucose-binding protein. The discussion also encompasses the pH-responsive systems and on-demand glucose administration systems activated by external triggers such as ultrasound, light, and temperature, with prospective opportunities and shortcomings.