Local control of Cre-regulated genetic modeling in vivo using wireless implantable optoelectronics

Effective modeling of chronic human diseases in vivo requires precise spatiotemporal regulation of molecular processes at defined tissue locations. Optogenetic and optoelectronic tools can provide such control but targeting internal organs such as the lungs remain challenging. To address this, we developed E-LightR-Cre recombinase, enabling precise, spatially restricted gene activation with no dark-state activity and robust blue-light responsiveness. To achieve local activation of E-LightR-Cre in specific organ sites, we engineered wireless, fully implantable optoelectronic devices enabling focal illumination of murine lungs with no discernible organ damage. The size of activated area is controlled by modulating light intensity and duration. Using implanted optoelectronic devices, we activated E-LightR-Cre in a selected area of mouse lungs and achieved local regulation of targeted genes. Light-regulated expression of oncogenic KRas-G12D mutant in mouse lungs induced local formation of oncogenic lesions. These results show that our protein engineering and adaptable optoelectronic approaches enable facile application of optogenetic tools for locally controlled disease modeling in vivo.