Boosting Long-Range Surface-Enhanced Raman Scattering on Plasmonic Nanohole Arrays for Ultrasensitive Detection of MiRNA

A fundamental challenge, particularly, in surface-enhanced Raman scattering (SERS) analysis is the detection of analytes that are distant from the sensing surface. To tackle this challenge, we herein report a long-range SERS (LR-SERS) substrate supporting an extension of electric field afforded by long-range surface plasmon resonance (LRSPR) excited in symmetrical dielectric environments. The LR-SERS substrate has a sandwich configuration with a triangle-shaped gold nanohole array embedded between two dielectrics with similar refractive indices (i.e., MgF₂ and water). The finite-difference time-domain simulation was applied to guide the design of the LR-SERS substrate, which was engineered to have a wavelength-matched LRSPR with 785 nm excitation. The simulations predict that the LR-SERS substrate exhibits great SERS enhancement at distances of more than 10 nm beyond its top surface, and the enhancement factor (E_F) has been improved by three orders of magnitude on LR-SERS substrates compared to that on conventional substrates. The experimental results show good agreement with the simulations, an E_F of 4.1 × 10⁵ remains available at 22 nm above the LR-SERS substrate surface. The LR-SERS substrate was further applied as a sensing platform to detect microRNA (miRNA) let-7a coupled with a hybridization chain reaction (HCR) strategy. The developed sensor displays a wide linear range from 10 aM to 1 nM and an ultralow detection limit of 8.5 aM, making it the most sensitive among the current detection strategies for miRNAs based on the SERS–HCR combination to the best of our knowledge.