Kinetically Arrested SERS‐Active Aggregates for Biosensing

There is great demand for biosensors capable of long-term, non-invasive monitoring of low analyte concentrations in various biofluids for diagnostics, personalized healthcare, and disease monitoring. However, biofluids present several challenges to biosensor sensing and stability on account of their complex composition and dynamic nature. Surface-enhanced Raman spectroscopy (SERS) offers ultra-high sensitivity, non-destructive, real-time monitoring, and non-invasive detection, ideal for sensing in complex media. Plasmonic gold nanoparticle (AuNP) SERS-active assemblies have been widely explored owning to their biocompatibility and tunable sensitivity based on AuNP morphology. Here, we employ thiolated poly(ethylene glycol) (PEG-SH) to produce kinetically trapped metastable AuNP:cucurbit[7]uril (CB[7]) aggregates containing robust nanogaps (ca. 1 nm), which have previously displayed strong, reproducible SERS signals at low concentrations. The AuNP:CB[7]:PEG aggregates maintain strong SERS-activity, demonstrating low concentration detection of a model Raman reporter and a bioanalyte in a range of biofluids. Moreover, the aggregates are highly tunable through facile modification of the PEG-SH chain length and grafting density and possess an encoded disassembly mechanism within their design highlighting the potential application of these aggregates for non-invasive in vivo long-term monitoring alongside future customized SERS biosensing applications.