Precise rewiring of corticospinal axons and spinal interneurons via near-infrared optogenetics for spinal cord injury treatment.

To date, precise restoration of proper connections between posttrauma axons and neurons following spinal cord injury (SCI) remains a substantial challenge. Here, we developed glutamate-linked upconversion nanoparticles (Glu-UCNP) to facilitate optogenetic control of axonal sprouting in SCI mice. After being specifically uptaken by the postsynaptic interneurons innervated by corticospinal tract (CST) axons, Glu-UCNP not only serves as internal light transducers that convert near-infrared light to visible light but also acts as nanobeacons that guide axonal sprouting toward postsynaptic neurons of glutamatergic synapses. This in situ optogenetic modulation successfully demonstrated the restoration of spinal motor circuits by rebuilding functional connections between CST axons and postsynaptic interneurons. It was corroborated by live-cell recording, immunofluorescence staining, in vivo Ca2+ imaging, and pellet-reaching tests. Transcriptome sequencing further elucidated the molecular network changes underlying this optogenetic modulation. These findings highlight the potential therapeutic applications of optogenetic modulation in the reassembly of neural circuits after SCI.