Materials and Carriers Development for Glucose-Responsive Insulin

ConspectusInsulin replacement therapy is an essential and effective treatment strategy for controlling the blood glucose level (BGL) of people without sufficient endogenous insulin production. However, insulin therapy faces challenges such as daily multiple injections and hypoglycemia risk arising from its narrow therapeutic index, which together leads to poor BGL control. Thus, glucose-responsive insulin delivery systems that can mimic β-cell function are developed to improve BGL control and reduce injection frequency. Glucose-responsive materials-based insulin delivery systems are competent in tightly controlling the BGL with an additional benefit of reducing the hypoglycemia risk. Glucose-responsive materials generally work together with three major glucose-sensing elements: glucose oxidase (GOx), phenylboronic acid (PBA), and glucose-binding molecules. Based on glucose-sensing elements, glucose-responsive materials are rationally designed to sense the change in glucose concentration or indirect signals associated with glucose fluctuation, such as pH, H2O2 concentration, and O2 level, and adjust their physical or chemical characteristics accordingly. Many advanced glucose-responsive materials have been developed along this line, aiming to achieve robust glucose-responsive insulin release performance and elevate their therapeutic outcome. These advanced materials mainly include organic materials such as biomacromolecules, synthetic polymers, polypeptides, liposomes, and inorganic materials such as calcium phosphate (Ca3(PO4)2) and metal organic frameworks (MOFs). Built on these glucose-responsive materials, other groups and we have developed various carriers such as hydrogels, micro/nanoparticles, liposomes, complexes, cell–drug conjugates, and microneedle (MN) array patches. These delivery systems can release insulin via glucose-stimulated swelling/contraction, dissolution, pore size change, charge reversal, and polymer deterioration. Also, these carriers are continuously under development to accelerate responsive rate, increase response index, and improve biocompatibility. Our group focuses on the synthesis of glucose-responsive materials and the design of glucose-responsive MN array patches, hydrogels, insulin complexes, and cell–drug conjugates for the treatment of diabetes in a dose-, spatial-, and temporal-controlled fashion. These closed-loop insulin delivery systems can respond to BGL alternation and secrete the correct amount of insulin accordingly. Also, MN array patches have the additional merits of reducing pain and easy administration.In this Account, we briefly introduce the glucose-responsive mechanisms and the relevant requirements of materials that can work cooperatively with these mechanisms. Then, we highlight our group's work in preparing various materials for constructing glucose-responsive carriers. We are mainly aiming to improve glucose-responsive properties, administration feasibility, and in vivo biocompatibility. The challenges and perspectives associated with glucose-responsive materials for clinical translation are also discussed. We envision that our glucose-responsive MN array patch for insulin release will facilitate the clinical use of glucose-responsive materials.