Substituent Effects Impact Surface Charge and Aggregation of Thiophenol-Labeled Gold Nanoparticles for SERS Biosensors

Nolan File, Joseph Carmicheal, Alexey V. Krasnoslobodtsev, Nicole C. Japp, Joshua J. Souchek, Sudesna Chakravarty, Michael A. Hollingsworth, Aaron R Sasson, Gopalakrishnan Natarajan, Prakash G. Kshirsagar, Maneesh Jain, Chihiro Hayashi, Wade M. Junker, Sukhwinder Kaur, Surinder K. Batra

Research output: Contribution to journalArticlepeer-review


SERS immunoassay biosensors hold immense potential for clinical diagnostics due to their high sensitivity and growing interest in multi-marker panels. However, their development has been hindered by difficulties in designing compatible extrinsic Raman labels. Prior studies have largely focused on spectroscopic characteristics in selecting Raman reporter molecules (RRMs) for multiplexing since the presence of well-differentiated spectra is essential for simultaneous detection. However, these candidates often induce aggregation of the gold nanoparticles used as SERS nanotags despite their similarity to other effective RRMs. Thus, an improved understanding of factors affecting the aggregation of RRM-coated gold nanoparticles is needed. Substituent electronic effects on particle stability were investigated using various para-substituted thiophenols. The inductive and resonant effects of functional group modifications were strongly correlated with nanoparticle surface charge and hence their stability. Treatment with thiophenols diminished the negative surface charge of citrate-stabilized gold nanoparticles, but electron-withdrawing substituents limited the magnitude of this diminishment. It is proposed that this phenomenon arises by affecting the interplay of competing sulfur binding modes. This has wide-reaching implications for the design of biosensors using thiol-modified gold surfaces. A proof-of-concept multiplexed SERS biosensor was designed according to these findings using the two thiophenol compounds with the most electron-withdrawing substitutions: NO2 and CN.

Original languageEnglish (US)
Article number25
Issue number1
StatePublished - Jan 2022


  • Aggregation
  • Immunoassay
  • Multiplexing
  • Nanoparticles
  • Raman reporter molecules
  • SERS

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biotechnology
  • Biomedical Engineering
  • Instrumentation
  • Engineering (miscellaneous)
  • Clinical Biochemistry


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