Mirror-Image L-DNA Aptamers Enable Stable In Vivo Dopamine Sensing

Long-term in vivo neurochemical sensing with aptamer-based electrochemical sensors is fundamentally limited by the enzymatic degradation of natural D-DNA aptamers and the instability of surface-confined sensing interfaces. Here, we generate a mirror-image L-DNA analogue of a dopamine-binding aptamer and show that chiral inversion preserves folding, affinity, and selectivity, as confirmed by circular dichroism, fluorescence binding assays, and molecular docking. Integration of this L-aptamer with a stabilized electrochemical conjugation on carbon-fiber microelectrodes yields a highly stable mirror-image molecular-electrical interface capable of sensitively transducing dopamine binding into quantitative electrochemical signals. Owing to its exceptional nuclease resistance, the L-aptamer sensor enables continuous dopamine monitoring in vivo for over 24 h─an order-of-magnitude improvement in signal over conventional D-aptamer sensors. Applied in Parkinson's disease mouse model, the sensor resolves pathological dopamine clearance defects. These results establish mirror-image nucleic acids, when coupled with engineered electrochemical interfaces, as effective components for durable bioelectronic sensing in vivo.