Clinically-Driven\nRapidly Developed Nanoparticle Corona\nfor Label-Free Cerebrospinal Fluid Leakage Detection

Rapid diagnosis of cerebrospinal\nfluid (CSF) leaks is critical\nas endoscopic endonasal skull base surgery gains global prominence.\nCurrent clinical methods such as endoscopic examination with and without\nintrathecal injection of fluorescent dye are invasive and rely on\nsubjective judgment by physicians, highlighting the clinical need\nfor label-free point-of-care (POC). However, a viable solution remains\nundeveloped due to the molecular complexity of CSF rhinorrhea mixed\nwith nasal discharge and the scarcity of specific biomarkers, delaying\nsensor development. In this study, we accelerated the development\nof a label-free CSF detection method for clinical use using a nanoparticle\ncorona. We engineered corona nanointerfaces on near-infrared (nIR)\nfluorescent single-walled carbon nanotubes (SWCNTs) through noncovalent\nfunctionalization with 12 custom-designed poly(ethylene glycol) (PEG)\nlipids. By high-throughput screening of the corona library for the\nCSF biomarker β-trace protein (βTP), we selected the optimal\ncorona, achieving a limit of detection (LOD) down to 1.46 mg/L, maintaining\nits selectivity even in human nasal discharge. Using molecular dynamics\nand docking simulations, we characterized the 3D morphology and βTP\nbinding energy of the optimal corona in a quantified way. The corona\nnanosensor accurately diagnosed CSF leakages from eight patients having\nlumbar drainage and one patient with CSF leakage due to diverse diseases\nwithout any sample preparations. By integrating the nanosensor with\ncustom-designed in vivo and in vitro form factors such as a camera\nand endoscope, we showed its potential for versatile and practical\nuse in clinical settings. This accelerated sensor development platform\ncan meet future urgent clinical demands for various diseases and conditions.