Light provides high
temporal precision for neuronal
modulations.
Small molecules are advantageous for neuronal modulation due to their
structural diversity, allowing them to suit versatile targets. However,
current optochemical methods release uncaged small molecules with
uniform concentrations in the irradiation area, which lack spatial
specificity as counterpart optogenetic methods from genetic encoding
for photosensitive proteins. Photocatalysis provides spatial specificity
by generating reactive species in the proximity of photocatalysts.
However, current photocatalytic methods use antibody-tagged heavy-metal
photocatalysts for spatial specificity, which are unsuitable for neuronal
applications. Here, we report a genetically encoded metal-free photocatalysis
method for the optochemical modulation of neurons via deboronative
hydroxylation. The genetically encoded photocatalysts generate doxorubicin,
a mitochondrial uncoupler, and baclofen by uncaging stable organoboronate
precursors. The mitochondria, nucleus, membrane, cytosol, and ER-targeted
drug delivery are achieved by this method. The distinct signaling
pathway dissection in a single projection is enabled by the dual optogenetic
and optochemical control of synaptic transmission. The itching signaling
pathway is investigated by photocatalytic uncaging under live-mice
skin for the first time by visible light irradiation. The cell-type-specific
release of baclofen reveals the GABABR activation on NaV1.8-expressing nociceptor terminals instead of pan peripheral
sensory neurons for itch alleviation in live mice.