Upconversion nanoparticles-loaded injectable supramolecular hydrogels for on-demand glycemic regulation by optogenetic GLP-1 release

Summary Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed the treatment of type 2 diabetes and obesity. However, their clinical applications suffer from frequent injections, systemic adverse effects, and the intrinsically passive characteristics of current sustained-release depots. Here, we present upconversion nanoparticles (UCNPs)-loaded injectable supramolecular hyaluronate (HA) hydrogels for on-demand glycemic regulation by optogenetic GLP-1 release. Upon transdermal near-infrared (NIR) irradiation, the UCNPs emit blue light that activates optogenetic cells and triggers GLP-1 secretion to control blood glucose levels. In model mice, with continuous glucose monitoring (CGM) using a sweat glucose sensor, a single subcutaneous injection enables NIR-triggered sustained regulation of blood glucose levels without detectable local inflammation or toxicity. Taken together, these findings establish a minimally invasive platform that couples the durability of injectable biomaterial depots with the temporal precision of light-triggered cell therapy for on-demand glycemic regulation.