From hotspots to hotspaces: Cascaded photonic-plasmonic coupling for SERS-based deep profiling of whole small extracellular vesicles.

The spatial confinement of electromagnetic hotspots (<15 nanometers) in plasmonic nanostructures fundamentally restricts their utility for probing large, heterogeneous targets across diverse material and biological systems. We introduce a cascaded photonic-plasmonic strategy that bridges far-field illumination and near-field enhancement by integrating dielectric silicon dioxide microspheres that form subdiffraction nanojets on a plasmonic, gold-coated silicon dioxide nanoarray. This dual-layer architecture generates spatially extended electromagnetic "hotspaces" exceeding 110 nanometers in lateral extent and sustaining analytical enhancement factors > 106, a regime inaccessible to conventional surface-enhanced Raman scattering (SERS) platforms. In silico simulations and experiments reveal ~20-fold enhancements in signal intensity and spatial reach compared to conventional nanoarrays. As a proof of concept, we demonstrate ultrasensitive, label-free classification of extracellular vesicles, 80 to 200 nm in diameter, derived from patients with colorectal cancer with 99.8% accuracy, surpassing traditional SERS (<87.5%). More broadly, this cascaded excitation strategy shifts the emphasis from nanogap optimization to the engineering of spatially extended fields through hybrid light-focusing architectures, enabling advances in spectroscopy, biosensing, nanophotonics, and diagnostics.