Tether-free optogenetic control of insulin secretion using an upconversion nanoparticle-doped hydrogel platform

Glucagon-like peptide-1 (GLP-1), as a molecular therapeutic, induces glucose-dependent stimulation of insulin secretion, which has drawn significant attention in treating type II diabetes. However, it always suffers from hurdles such as short half-lives or instability. Thus, producing such therapeutics endogenously, as and when needed, is beneficial. Optogenetics-based production of GLP-1 offers an attractive alternative, wherein, the cell lines such as HEK293T can be genetically modified to bring the expression of the gene of interest under visible light control. However, the need for blue light for activation necessitates the implantation of invasive optical fibers owing to high tissue scattering and low depth of penetration through biological tissue at this wavelength. Here, we overcome this problem by proposing an upconversion nanoparticle (UCNP)-based system. HEK293T cells, rewired to produce GLP-1 under blue light illumination, were co-encapsulated with UCNPs in a hydrogel. The UCNPs act as near-infrared (NIR) to blue light nano-transducers, allowing deep penetration toward implementing a tether-free optogenetic gene expression platform. This platform is particularly powerful for thick gel implants (>3 mm) that cannot be illuminated throughout using a blue light source. Moreover, the GLP-1 produced in this platform was sufficient to increase insulin secretion in rat insulinoma cells, providing a powerful and controllable therapeutic tool for diabetes.