Single-Molecule Detection via Pore Nanoconfinement of Covalent Organic Frameworks for Surface-Enhanced Raman Scattering.

Surface-enhanced Raman scattering (SERS) offers significant advantages for single-molecule detection. However, stochastic molecular motion makes it challenging to consistently capture signals from single-molecule binding events, particularly in complex environments. Herein, we propose a novel SERS system via the pore nanoconfinement effect of covalent organic frameworks (COFs) to achieve reliable single-molecule detection. The self-assembled COF thin films on SERS metal substrates (Au/Ag) create a nanogap of 3 nm, allowing electric field enhancement. By precise tuning of the COF shell thickness, a molecular-scale pore volume is formed, effectively trapping individual molecules from molecular aggregates. Furthermore, the strong intermolecular forces within the COF pores significantly enhance the residence time of individual molecules, thereby increasing the probability of detecting single-molecule binding events. This innovative approach ensures consistent and reliable SERS single-molecule detection in complex mixtures, paving the way for advanced applications in biochemical sensing and diagnostics.