Ultrasensitive and Selective Iontronic H 2 O 2 Nanosensor Reveals the Biphasic Redox Dynamics Invoked by l -DOPA at a Single-Cell Level

As the gold-standard therapy for Parkinson's disease, 3,4-dihydroxyphenylalanine (l-DOPA) alleviates motor symptoms but paradoxically induces concentration-dependent dyskinesia and oxidative stress due to redox dynamics involving hydrogen peroxide (H₂O₂) generation. While vitamin B6 (VB6) modulates l-DOPA metabolism and redox balance, its pharmacodynamic interplay with l-DOPA remains controversial, hindered by methodological limitations in resolving intracellular H₂O₂ dynamics. Here, we developed an ultrasensitive H₂O₂ iontronic nanosensor by integrating a hydrogel-filled nanopipette and a dual-amplification strategy, enabling in situ monitoring of dynamic redox changes induced by l-DOPA and VB6. By leveraging oxygen nanobubbles as transducers and amplifying signals with nanoconfined ion transport and the electrophoresis-like technique for catalase preconcentration, the sensor features ultrasensitive H₂O₂ detection (LOD 1.76 nM) and high spatiotemporal resolution. With the as-developed sensor, we uncovered l-DOPA's biphasic effects: neuroprotection in physiological concentration (10 μM, reduced oxidative eustress by 20%) and neurotoxicity in pathological concentration (100 μM, elevated oxidative distress to 20-fold). Notably, VB6 coadministration exacerbated oxidative stress, revealing its synergistic enhancement effect in l-DOPA neurotoxicity. This work not only provides a novel methodology for highly sensitive iontronic sensors but also enables in situ monitoring of redox dynamics of physiological and pathological processes.