A Precision‐Delivered Singlet Oxygen Generator With an Inbuilt Safety Switch for Induction of Pancreatic Beta Cell Stress and Death

Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic beta cells, leading to insulin dependence. Preclinical models have been instrumental in advancing our understanding of the pathogenesis and treatment of T1D. Chemical agents such as streptozotocin or alloxan are widely used to induce beta cell destruction without the need for genetic alteration. However, streptozotocin and alloxan exhibit variable efficacy, can be taken up non‐specifically into other organs, and possess carcinogenic properties. As such, there is a need for more specific and less toxic models of beta cell stress. Here, we design and evaluate ROXendin668, a glucagon‐like peptide‐1 receptor (GLP1R) agonist coupled to a singlet oxygen ( 1 O 2 ) sensitizer. ROXendin668 targets pancreatic beta cells through engagement of GLP1R and potentially GCGR, followed by red light‐controlled generation of 1 O 2 . Upon illumination, ROXendin668 selectively ablates MIN6 β‐cells and primary islet β‐cells and induces localized β‐cell stress in vivo after systemic delivery. Thus, ROXendin668 represents a precise, controllable, and potentially safer alternative to existing chemical models of beta cell stress.