Epilepsy is a frequent neurological disorder affecting about 1% of the general population, with 30% of patients that are resistant to antiepileptic drugs. In the last decade, optogenetics has emerged as an efficient antiepileptic strategy, although the difficulty of illuminating multiple and deep areas of the brain still poses translational challenges. In this scenario, the search of alternative light sources is strongly needed. Here, we developed a closed-loop chemo-optogenetic nanomachine, named pH-sensitive inhibitory luminopsin (pHIL), composed of a luciferase-based light generator, a fluorescent sensor of intracellular pH (E2GFP), and an optogenetic actuator (halorhodopsin) for silencing neuronal activity. pHIL undergoes bioluminescence resonance energy transfer between luciferase and the first E2GFP acceptor which, under conditions of acidic pH, activates halorhodopsin by fluorescence resonance energy transfer. In HEK293 cells, the pHIL sensor-actuator was effective in inducing hyperpolarization in response to acidic pH shifts. In primary neurons, pHIL sensed the intracellular pH drop associated with hyperactivity and optogenetically aborted epileptic-like paroxysmal activity elicited by the administration of convulsants. The expression of pHIL in excitatory neurons of the hippocampus was effective in decreasing the occurrence and duration and increasing the latency of acute pilocarpine-induced tonic-clonic seizures in vivo. The results indicate that pHIL represents a potentially promising gene therapy approach to treat drug-refractory epilepsy independent of the specific etiology. The research was funded by PRIN 2020WMSNBL/P2022EZ9LN and Ministry of Health PNRR-MR1-2022-12376528.