Camouflage Nanoparticles Enable in Situ Bioluminescence-Driven Optogenetic Therapy of Retinoblastoma

Optogenetic therapy has emerged as a promising technique for the treatment of ocular diseases; however, most optogenetic tools rely on external blue light to activate the photoswitch, whose relatively strong phototoxicity may induce retinal damage. Herein, we present the demonstration of camouflage nanoparticle-based vectors for in situ bioluminescence-driven optogenetic therapy of retinoblastoma. In biomimetic vectors, the photoreceptor CRY2 and its interacting partner CIB1 plasmid are camouflaged with folic acid ligands and luciferase NanoLuc-modified macrophage membranes. To conduct proof-of-concept research, this study employs a mouse model of retinoblastoma. In comparison to external blue light irradiation, the developed system enables an in situ bioluminescence-activated apoptotic pathway to inhibit tumor growth with greater therapeutic efficacy, resulting in a significant reduction in ocular tumor size. Furthermore, unlike external blue light irradiation, which causes retinal damage and corneal neovascularization, the camouflage nanoparticle-based optogenetic system maintains retinal structural integrity while avoiding corneal neovascularization.