Bioengineered Spider Silk Activates GPCRs for Targeted Therapeutic Delivery

G-protein-coupled receptors (GPCRs) are a vast family of cell surface receptors crucial for numerous physiological processes and represent the largest class of drug targets. However, current therapeutic strategies often struggle with achieving precise, cell-specific activation and sustained drug release, leading to off-target effects and frequent dosing. This study addresses this by developing a novel bioengineered spider silk platform designed for highly targeted and prolonged activation of specific GPCRs.

The bioengineered spider silk successfully presented the peptide ligand, demonstrating stable and specific binding to the target GPCRs in vitro. Calcium flux assays revealed a dose-dependent increase in GPCR activation, with the functionalized silk showing an EC50 of 120 nM, comparable to the free ligand but with significantly sustained activation over 24 hours. The most significant finding was that the silk-ligand construct achieved 85% of the maximal activation observed with the free ligand, but maintained activation for 3-fold longer, indicating enhanced stability and prolonged signaling. In vivo, diabetic mice treated with the silk construct exhibited a 35% reduction in fasting blood glucose levels compared to control groups (p<0.001), alongside a 2.1-fold increase in insulin secretion after 7 days of treatment.