In Vivo Reprogramming Dysfunctional Retinal Ganglion Cells and Visual-phototransduction via Wireless Charging...

Gene therapy offers a promising treatment for Leber's hereditary optic neuropathy (LHON), a disease of retinal ganglion cell (RGC) degeneration with severe vision loss caused by mitochondria-NADH dehydrogenase 4 (MT-ND4) mutations. However, optimizing mitochondria-targeted gene delivery to promote RGC regeneration and visual-photoreception recovery remains challenging in LHON. Here, mitochondria-targeted wireless charging gold nanoparticles (WCGs), doubling as a wireless charging-mediated gene-delivery platform and electric stimulus-restored phototransduction, are developed for LHON treatment. Upon high-frequency magnetic field (HFMF) irradiation, WCGs enhanced MT-ND4 transfection efficiency, restored complex I activity and mitochondrial homeostasis in vitro, and further promoted RGC neurite outgrowth in LHON patient-derived iPSC-differentiated retinal organoids. Wireless charging combined with electric stimulation also facilitated in vivo gene delivery, effectively promoting neuronal recovery, preventing RGC degeneration, suppressing inflammation, and enhancing retinal electrophysiological function in the damaged retinas of LHON mice. Furthermore, single-cell RNA sequencing and spatiotemporal transcriptomic analysis revealed that HFMF-treatment reprograms Müller glia to enhance dendritic development, restore mitochondrial function, and express phototransduction genes to support photoreceptor function in vivo. Finally, functional retinal-optic-electrophysiological findings with spatiotemporal transcriptomic analysis at the single-cell level support that HFMF synergized with WCG/hND4 therapy, promoting retinal repairment with RGC neurite regeneration and recovering visual phototransduction in LHON mouse models.