Transgene-Free Photothermal Enhancement of Glucose-Adaptive Insulin Secretion by Amplifying Ca2+ Oscillations

Precise and on-demand regulation of cellular secretion is essential for effective and safe therapeutic intervention; however, most open-loop secretion strategies have limited integration of physiological feedback and require the introduction of synthetic genetic circuits, thereby constraining adaptive secretion control and increasing system complexity. Here, we present a transgene-free photothermal strategy for enhancing insulin secretion that integrates externally programmable open-loop control with physiology-coupled feedback regulation by directly leveraging endogenous voltage-gated Ca2+ channels (VGCCs), Ca2+-dependent exocytotic machinery, and the glucose-stimulated insulin secretion (GSIS) feedback loop. Mesoporous polydopamine nanoparticles functionalized with a near-infrared absorber (mPDA-IR) are coupled with MIN6 pancreatic β cells, which are subcutaneously implanted into type 1 diabetic mice. Under hyperglycemic conditions, mild photothermal activation (<42 °C) enhances membrane depolarization and VGCC activation, thereby amplifying Ca2+ oscillations and driving Ca2+-dependent insulin secretion. In vitro, photothermal modulation reproducibly evokes Ca2+ responses and propagates intercellular Ca2+ waves in both two-dimensional cultures and three-dimensional pseudoislets. Notably, insulin secretion is minimal under glucose-free conditions but robust under hyperglycemia. In vivo, a single photothermal stimulation adaptively enhances insulin secretion and efficiently restores blood glucose levels from severe hyperglycemia (≈550 mg/dL) to normoglycemia in type 1 diabetic mice. Collectively, this work establishes a transgene-free, externally actuated yet physiologically self-regulated strategy for precise regulation of cellular secretion.