Continuous, Week-Long, Seconds-Resolved <i>In Vivo</i> Drug Measurements Performed with a Xenonucleic Acid-Employing Electrochemical, Aptamer-Based Sensor

The ability to monitor drug and biomarker concentrations in the body continuously and in real time could transform our understanding of physiology, enhance the diagnosis and monitoring of disease, and enable high-precision, truly personalized drug dosing. Toward this goal, we are developing electrochemical aptamer-based (EAB) sensors, the only real-time monitoring technology yet shown able to measure molecules as diverse as small molecule drugs to protein biomarkers <i>in situ</i> in the veins, brains, and peripheral tissues of live subjects. This advance notwithstanding, a significant challenge nevertheless remains: to date, degradation of their target-recognizing aptamer has limited the demonstrated, <i>in vivo</i> operation of EAB sensors to less than 24 h, reducing the platform's clinical and scientific utility. Notably, for example, the continuous glucose monitor did not come into widespread clinical use until it reached an <i>in vivo</i> duration of 5 days, with current models achieving an operational duration of 2 weeks. Thus motivated, here we use a non-natural, more nuclease-resistant "xenonucleic" acid (XNA) aptamer to extend the continuous, <i>in vivo</i> operation of EAB sensors to 1 week, with the latter encompassing >47,000 real-time, 12.8 s-resolved measurements. Moreover, we have reached this operational duration without employing protective membranes, which can harm sensor performance and complicate sensor fabrication and insertion. The week-long <i>in vivo</i> operation demonstrated here represents a crucial milestone for clinical adoption and experimental flexibility, marking a shift from short-term testing toward robust, long-duration, real-time molecular measurements.