A Lifetime Nanosensor for In Vivo pH Quantitative Imaging and Monitoring

Non-invasive, in vivo quantitative imaging for long-term biomarker monitoring is crucial for elucidating disease mechanisms, advancing precision medicine, and transforming diagnostics and therapeutic strategies. However, developing chemical sensors for sustained in vivo quantitative monitoring despite sensor concentration fluctuations, excitation variability, and tissue interference remains a major challenge. Here, a long-lifetime nanosensor based on a lanthanide-dye nanocomposite is presented that overcomes these limitations, enabling precise quantitative in vivo pH monitoring. Benefiting from a 64-fold reversible change in the dye's molar extinction coefficient, this nanosensor enables the dynamic tuning of reversible non-radiative energy transfer (RNET) efficiency (6.42%-35.23%) and luminescence lifetime (265-383 µs). This nanosensor enables 4 h of monitoring of gastrointestinal pH dynamics in mice following proton pump inhibitor (PPI) administration, offering new insights into pharmacodynamic effects across different administration routes and dosages and inter-individual variability in drug efficacy. Moreover, coordination with lanthanide nanocrystals induces a significant shift in the dye's pK_a, highlighting the importance of nanomaterial interface engineering. This work establishes a versatile platform for in vivo diagnostics and therapeutic monitoring, marking a significant step forward in precision medicine.