A Hybrid Fluorescence-Optoelectronic Nanoscale Sensor for the Early Diagnosis of Tau Pathology

Early detection of tauopathies is crucial for identifying disease onset and enabling effective management of disorders such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD). Here, we present a highly sensitive and specific method for detecting early, non-fibrillar Tau oligomers before tangle formation. Among a series of synthesized quantum dots, only the nitrogen–phosphorus-doped carbon quantum dots (N,P-CQDs) demonstrated the desired specificity. These N,P-CQDs are derived from phosphoserine dimers linked through an unusual phosphate ester bond rather than a conventional amide bond. They are characterized as 3–7 nm in diameter and emit bright red fluorescence at 600 nm, enabling the specific detection of toxic oligomeric and fibrillar Tau species in vitro and in tau pathogenic brain tissues and cerebrospinal fluid (CSF). The N,P-CQD nanoprobe offers an advantage over conventional Thioflavin T staining because of its large 300-nm Stokes shift between excitation and emission, which minimizes background noise. The calculated fluorescence half-life (t1/2) was 1.66 μs, with a fluorescence decay time (τ) of approximately 3.0 μs, demonstrating the potential of the probe for ultrasensitive detection. The proposed integrated bio-opto-electronic platform, leveraging the specific and highly sensitive spectral response of N,P-CQD-functionalized nanoneedles to oligomeric tau aggregates, as determined in conjunction with biolayer interferometry (BLI), establishes a foundation for a real-time, minimally invasive future diagnostic tool for the detection of neurodegenerative disorders.