Glucose-Responsive Materials for Smart Insulin Delivery: From Protein-Based to Protein-Free Design.

Over the last four decades, glucose-responsive materials have emerged as promising candidates for developing smart insulin delivery systems, offering an alternative approach to treating diabetes. These materials replicate the pancreas's natural "closed loop" insulin secretion function by detecting changes in blood glucose levels and releasing insulin accordingly. This perspective highlights the evolution of glucose-responsive materials from protein-based materials, such as glucose oxidase (GOx), and glucose-binding proteins, such as concanavalin A (ConA), to protein-free materials, including phenylboronic acid (PBA) and their applications in smart insulin delivery. We first describe protein-based glucose-responsive systems that depend on different macromolecules, including enzymes and proteins, that interact directly with glucose to promote insulin release. However, these systems encounter significant stability, scalability, and immunogenicity challenges. In contrast, protein-free systems include hydrogels, nanogels/microgels, and microneedle patches, offering long-term stability and storability. In this direction, we discuss the design principles, mechanisms of glucose/pH sensitivity, and the disintegration of both protein-based and protein-free systems into different glucose environments. Finally, we outline the key challenges, potential solutions, and prospects for developing smart insulin delivery systems.