Advances in injectable and transdermal glucose-responsive insulin delivery systems

To address the core limitations of conventional insulin therapy, including delayed glycemic control and the frequent risk of hypoglycemia, the development of glucose-responsive insulin delivery systems capable of dynamically sensing blood glucose levels and releasing insulin on demand has emerged as a pivotal strategy. Based on their underlying sensing mechanisms, these systems are generally classified into three categories: those utilizing glucose oxidase, glucose-binding molecules, and phenylboronic acid. From the perspective of administration routes, injectable and transdermal delivery are the two primary approaches for glucose-responsive insulin. Injectable glucose-responsive insulin delivery systems are highly compatible with existing clinical practices, primarily relying on glucose-responsive carriers to regulate the insulin release rate and achieve stable and efficient bioavailability. Transdermal glucose-responsive insulin delivery systems utilize glucose-responsive microneedle arrays to penetrate the skin stratum corneum and precisely control the rate of insulin release, allowing for sufficient insulin delivery under almost painless conditions. This review systematically summarizes recent advances in both injectable and transdermal glucose-responsive insulin delivery systems, with a focus on carrier design strategies, glucose-responsive release mechanisms, and evolutionary pathways of preparation techniques. It also highlights the contributions of these systems toward improved glucose-responsiveness, therapeutic safety, biocompatibility, and patient adherence. Furthermore, challenges and future prospects for clinical translation are discussed. This overview is expected to provide valuable insights for further research and development in this field.