Electrode multiplexing enables scalable continuous molecular monitoring in interstitial fluid.

Continuous molecular monitoring in interstitial fluid could transform the real-time decoding of human physiology, but current wearable bioelectronics remain fundamentally constrained by hardware scaling, where each additional analyte typically requires dedicated sensing electrodes and circuitry. Here, we introduce an electrode multiplexing architecture that enables continuous multiplexed monitoring without increasing the number of electrodes. Central to this strategy is a dynamically reconfigurable ion-selective electrode that alternates between potentiometric sensing and counter electrode operation. This allows a single electrode to support multiple electrochemical modalities. Integrated with a nanoengineered gold nanoparticle-MXene interface and a microneedle-based wearable platform, the system enables continuous monitoring of glucose, lactate, and potassium ions in interstitial fluid with high sensitivity and operational stability through a wireless multiplexed sensing architecture (sensitivities of the glucose, lactate, and K+ sensors were 6.16 nA/mM, -1.77 nA/mM, and 55.86 mV/decade, respectively). The multiplexed sensor maintains stable electrochemical performance after repeated role-switching cycles while preserving ion sensitivity. Wireless in vivo monitoring in rats captured dynamic metabolic fluctuations with strong agreement to blood-based measurements, while human serum analysis demonstrated high clinical consistency across all analytes. By decoupling sensing dimensionality from hardware complexity, this work establishes electrode multiplexing as a scalable design principle for next-generation wearable bioelectronics and continuous molecular monitoring.