Resilient nanostructured bioanalytic microneedle longitudinally monitors preclinical renal and hepatic drug clearance and dysfunction

Wearable microneedle biosensors promise real-time molecular monitoring for precision medicine but are limited by low sensitivity and tissue abrasion. Overcoming these challenges, we recast electrode functionality not merely as a sensing substrate but as a mechanism for resilient, high signal-to-noise ratio (SNR) measurements in tissue. Our microneedle-based resilient nanostructured bioelectrode (RNB) is fabricated using a bilayer process that strengthens the electrode with a micrometer-thick gold adhesion layer and reduces fabrication-induced stress through controlled dealloying. The resulting RNBs are corrosion resistant, stable over a wide potential window, and have an artifact-free, nanocavity-textured interface. They integrate receptor-based electrochemical biosensors with enhanced SNR through increased active area, diffusion, and antifouling while remaining abrasion immune in megapascal-stiff tissues. The RNB extended in vivo biosensor lifetime for pharmacokinetics monitoring to 6 days in a freely moving rat. Paired with a blood-interstitial fluid equilibrium-based bioanalytical framework, the RNB accurately derived blood-equivalent pharmacokinetic parameters, enabling not only precision dosing of narrow therapeutic index drugs but also the direct assessment of hepatic and renal clearance. In hepatic studies, the RNB revealed delayed clearance of a chemotherapeutic (irinotecan) in liver-damaged models. In renal studies, RNB recordings correlated with blood antibiotic pharmacokinetics across chronic kidney disease severities. The RNB detected renal impairment earlier than conventional biomarker thresholds through drug clearance quantification and captured recovery under therapeutic intervention. These results establish the RNB as a viable microneedle platform for high-fidelity in vivo deployment of electrochemical biosensors, enabling minimally invasive, longitudinal monitoring of low-concentration analytes and real-time assessment of organ function.