Label-free fiber-optic cascade sensor for rapid and ultrasensitive serum folate quantification.

Fiber-optic biosensors based on interferometric structures have attracted considerable attention for rapid and label-free biomarker detection; however, achieving high sensitivity while maintaining practical applicability in complex biological matrices remains challenging. Here, we develop a tapered seven-core fiber (TSCF)-based interferometric biosensor for highly sensitive detection of serum folate. The TSCF cascade architecture generates multiple coupled interference peaks within a compact spectral window, enabling multi-point spectral validation and enhanced evanescent-field interaction. Combined with covalent immobilization of folate-binding protein (FBP) as the recognition layer, the optimized sensor exhibits a refractive-index sensitivity of 1352.1 nm/RIU and a folate sensitivity of 0.118 nm/(ng/mL), achieving a limit of detection of 0.75 ng/mL with a rapid 5-min assay time. The sensor shows excellent linearity (R2 > 0.98) across the range of 0-50 ng/mL and reliable regeneration capability over multiple cycles. Furthermore, quantitative analysis of ten clinical serum samples demonstrates strong concordance with a commercial chemiluminescence assay, demonstrating reliable analytical performance in complex matrices. This work expands tapered multicore fiber interferometry toward label-free small-molecule metabolite quantification, offering a cost-effective platform for clinical folate monitoring.