Photonic Crystal-Enhanced Surface-Enhanced Raman Scattering Biosensor with an Amphipathic Dendritic Supermolecule Probe for Direct Plasma Exosome Detection

Exosomes hold great promise for tumor diagnosis, but their efficient isolation and sensitive in situ detection from biofluids remain challenging. Surface-enhanced Raman scattering (SERS) is an ideal solution due to its high sensitivity, yet conventional SERS biosensors face a trade-off between complex nanostructures for strong hotspots and practical fabrication. Here, we developed a novel strategy combining a highly stable large-sized opal photonic crystal (OPC) substrate with an amphipathic dendritic supermolecule probe (ADSP) for exosome capture and detection. The OPC substrate enhances SERS performance by modulating incident light, enabling a simple Au nanolayer to achieve detection limits as low as 1 × 10 –9 M. Meanwhile, ADSP ensures efficient exosome capture from plasma. Together, this approach allows direct isolation and sensitive in situ detection using a structurally simple device. Significant differences between patient and healthy donor groups were observed in practical sample detection, highlighting the potential of this exosome capture and detection platform for clinical applications.