Spatiotemporally Precise Chemical Neuromodulation through MOF-Mediated Near-Infrared Control of Endogenous Signaling

Chemical neuromodulation offers a physiologically relevant approach to manipulate neural functions, yet current methods suffer from poor spatiotemporal precision, cargo instability, or requirements for genetic modification. Here, we report a near-infrared (NIR) light-controlled platform for on-demand nitric oxide (NO) delivery to neurons, using upconversion nanoparticles (UCNPs) coated with metal-organic framework shells covalently loaded with photolabile NO donors (UCNP@MOF-NO). The core-shell architecture exploits NIR-to-UV upconversion to photolytically release NO with spatiotemporal precision in deep brain regions, thereby modulating neuronal activity through endogenous signaling pathways. Covalent conjugation prevents small-molecule leakage, ensuring stability for over 1 week. Quantitative single-cell amperometric measurements reveal stimulus-evoked exocytosis in PC12 cells, while in vivo electrophysiological recordings demonstrate a ∼70% increase in spike firing frequency upon NIR irradiation. This work demonstrates NO-mediated neuromodulation at the single-cell level via endogenous signaling pathways, addresses fundamental challenges in modulating neurochemical signaling, and provides an alternative strategy for chemical neuromodulation.