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. 2025 Jul 11;10(28):30651–30659. doi: 10.1021/acsomega.5c02638

Sensitive SERS Platform for the Detection of Staphylococcus aureus via Freezing SERS Tags and Core–Shell Aptamer-Au@Fe3O4 Nanoparticles

Mingming Zheng †, Yunju Xiao ‡, Wenzhe Zhang †, Sirui Lv †, Liye Sun †, Qi Wang †, Junfang Zhu §,∥, Lei Chen †, Hong Lin †,*, Shihua Luo §,∥,*
PMCID: PMC12290702  PMID: 40727747

Abstract

The detection of Staphylococcus aureus is crucial for the diagnosis and treatment of infectious diseases. However, developing a simple and sensitive method for S. aureus detection remains challenging. Herein, we propose a sensitive surface-enhanced Raman spectroscopy (SERS) platform for the detection of S. aureus using core–shell aptamer-Au@Fe3O4 nanoparticles (Fe3O4–Au@apt) and freezing SERS tags. Core–shell Au@Fe3O4 magnetic nanoparticles were modified with S. aureusspecific primary aptamers for precise and efficient capture of S. aureus, followed by modification with large amounts of secondary aptamers and tetramercaptobenzoic acid through freezing. The proposed SERS platform demonstrated significant sensitivity toward S. aureus, with a limit of detection of 6.91 CFU/mL, which demonstrates 99.25 times higher sensitivity than conventional SERS tags. Additionally, the proposed SERS platform achieved good recovery rates in human urine and serum samples, ranging from 97.7% to 104.0% and 90.5% to 104.7%. The findings of the study suggest that the proposed SERS platform holds promise for the rapid and efficient detection of pathogenic bacteria.

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1. Introduction

Staphylococcus aureus is a common Gram-positive bacterium responsible for a variety of serious human infections, including abscesses, sepsis, and arthritis. Its rapid and sensitive detection is crucial for effective control of clinical infections. , Currently, common detection methods for S. aureus include bacterial culture, immunoassays, and molecular techniques, , with the former considered to be the gold standard for pathogen detection, although such methods typically take 2 to 4 days to obtain results. Enzyme-linked immunosorbent assays (ELISA), which are antibody-dependent, require laborious and complex sample preparation processes and expensive antibody reagents. − Moreover, molecular diagnostic tests such as polymerase chain reaction and metagenomic next-generation sequencing have excellent pathogen detection sensitivity but are costly and involve intricate testing procedures. , Therefore, developing a rapid, sensitive, and cost-effective detection method for S. aureus is of significant importance.

Currently, gold nanoparticle (AuNP)-based surface-enhanced Raman scattering (SERS) tags with rapid response can provide amplified, quantifiable, and stable Raman signals for pathogen detection. − For instance, Shen et al. proposed self-assembled nanogapped SERS tags (Si@Au/Au) for the simultaneous detection of Streptococcus pneumoniae and viruses in real clinical samples. Xiao et al. developed cyclic DNA nanostructure@AuNP tags for the sensitive detection of Escherichia coli O157:H7. Nevertheless, AuNP-based SERS tags have several limitations despite their superior analytical performance, including time-consuming and labor-intensive preparation procedures, , limited loading capacity and complex aptamer screening process, , and their stability in complex sample environments when Raman reporter molecules are directly assembled on the AuNP surface. In recent years, a simplified, rapid, and reagent-free freezing approach was proposed for DNA immobilization on AuNPs. , However, few studies have explored the preparation of SERS tags via freezing to date. In this paper, we successfully engineered SERS tags via the freezing-induced conjugation of aptamers and tetramercaptobenzoic acid (4-MBA)-functionalized AuNPs using a single-step, high-stability labeling method. Compared to other methods, this technique is one of the simplest, fastest, and most cost-effective approaches for constructing AuNP SERS tags (Table S1). Notably, these SERS tags exhibited 2.28-times higher SERS signal intensity than conventional preparation methods when detecting S. aureus, demonstrating substantial potential for bacterial detection.

Moreover, Au-coated magnetic nanoparticles (MNPs) have been widely studied as SERS-active substrates owing to their tunable hotspots and biocompatibility. − When conjugated with biomolecular recognition elements such as antibodies, aptamers, or antibiotics, MNPs become highly effective in isolating and capturing target analytes from intricate sample environments. Herein, we proposed that a sensitive and rapid detection platform for S. aureus was developed using core–shell Fe3O4–Au@apt MNPs and freezing aptamer/MBA/AuNP SERS tags. These SERS tags were rapidly synthesized in 10 min via a low-temperature coincubation method, which demonstrates its high stability and specificity toward S. aureus. Fe3O4–Au@apt MNPs were utilized to capture S. aureus efficiently. The platform demonstrated excellent sensitivity and a broad linear detection range for S. aureus by utilizing both cofreezing SERS tags and Fe3O4–Au@apt MNPs. By utilizing both cofreezing SERS tags and Fe3O4–Au@apt MNPs, the platform exhibited high sensitivity and a wide linear range for the detection of S. aureus. The SERS biosensor platform we propose will provide new insights for the rapid and accurate detection of S. aureus in the future.

2. Experimental Section

2.1. Materials and Reagents

Tetramercaptobenzoic acid (4-MBA) and branched polyethylenimine (PEI, MW 25 kDa) were obtained from Sigma-Aldrich (USA). Chloroauric acid tetrahydrate (HAuCl4·4H2O), phosphate-buffered saline (PBS), sodium borohydride (NaBH4), and hydroxylamine hydrochloride (NH2OH·HCl) were provided by Sinopharm Chemical Reagent Co. (Shanghai, China). ATCC reference strain of S. aureus (ATCC 25923), S. typhimurium, Staphylococcus epidermidis, Acinetobacter baumannii, and K. pneumonia was provided by Laboratory Medicine, Guangdong Provincial People’s Hospital. Aptamer probes of S. aureus were synthesized from Sangon Inc. (Shanghai, China); the sequences were as follows in Table S2 instruments and measurements.

Fe3O4 MNPs and Fe3O4–Au@apt were imaged by using transmission electron microscopy (TEM) with an FEI Talos F200X microscope (FEI Ltd., USA). The zeta potential of Fe3O4 MNPs and Fe3O4–Au@apt was detected by the Malvern Zetasizer Nano ZS90 (Marvin Panaco Ltd., UK). A Thermo Fisher Scientific, USA’s Multiskan GO Microplate Reader was used to conduct UV–vis absorption spectroscopy. A Renishaw inVia-Qontor Raman Microscope (Renishaw, UK) was used to gather the SERS spectra. The 785 nm laser with a power of 300 mW was chosen in this work, and the laser power on the surface of the sample was 0.9 mW.

2.2. Preparation of Fe3O4–Au@apt MNPs

The Fe3O4–Au was constructed based on the previous report; Fe3O4–Au@apt was constructed by a simple and rapid low temperature coincubation method. Briefly, we mixed primary aptamers (100 μM, 10 μL) and Fe3O4–Au (160 nm, 100 μL) together in a certain proportion and shook evenly and then froze them at −80 °C for at least 10 min. After thawing at room temperature, the mixture was enriched with a magnet and washed three times with ddH2O. Finally, the aptamer-modified Fe3O4–Au was constructed and stored at 4 °C until use.

2.3. Modification of Aptamer/4-MBA Cofunctionalized SERS Tags

AuNPs (45 nm) were synthesized according to a prior report. Aptamer/4-MBA cofunctionalized SERS tags were constructed based on the rapidly prepared SERS tags method. Briefly, we mixed AuNP (45 nm, 100 μL), secondary aptamers (100 μM, 1 μL), and the Raman reporter (4-MBA, 10 mM, 1 μL) together. Then, the mixture was shaken evenly and kept at −80 °C until ice crystals formed. After thawing at room temperature, the mixture was centrifuged (5600 rpm, 10 min) and washed with ddH2O three times. Finally, aptamer/4-MBA cofunctionalized SERS tags were resuspended in 100 μL of phosphate buffer (2 mM, pH 7.4) and stored at 4 °C.

2.4. SERS Detection of S. aureus

Different concentrations of S. aureus (10, 1 × 102, 1 × 103, 1 × 104, 1 × 105, 1 × 106, 1 × 107 CFU/mL) were incubated with Fe3O4–Au@apt in a thermostatic oscillator for 40 min at 37 °C. Then, the Fe3O4–Au@apt/S. aureus complex was washed. Afterward, SERS tags and Fe3O4–Au@apt/S. aureus complexes were shaken for 50 min. The formed Fe3O4–Au@apt/S. aureus tag sandwich complex was washed with ddH2O and dropped onto a Si chip, after the sample was completely dried, and Raman signals of the complex were collected. In this work, we used a 785 nm laser with a power of 300 mW, and the transmittance power of the instrument was 60%. During the detection process, we chose a 0.5% attenuation power. Therefore, the laser power on the surface of the sample was calculated as 300 mW × 60% × 0.5% = 0.9 mW.

2.5. Analytical Performance of the SERS Platform

For evaluation of the specificity of the SERS platform, a predetermined quantity of S. aureus, S. typhi, S. epidermidis, A. baumannii, and K. pneumonia were spiked into human blood and urine, respectively, for three replicates. A predetermined quantity of bacteria and core–shell aptamer-Au@Fe3O4 were added to human serum and urine samples, respectively, and rapidly magnetic separation was performed after 40 min. It was then eluted with ddH2O. The rapid preparation of SERS tag reaction was then added for 50 min, and then the SERS signal was collected by rapid magnetic separation. We validated the specific detection of S. aureus in real samples with 4 nontarget strains.

3. Results and Discussion

3.1. Design Principles and Detection Strategies of the SERS Platforms

The principle of the high-performance SERS platform for detecting S. aureus is illustrated in Figure of this study. Sulfhydryl-modified aptamer and Raman reporter (4-MBA) SERS tags were formed using a rapidly prepared low-temperature coincubation method (Figure A). Primary aptamers and secondary aptamers were selected from previously published articles, respectively. , Secondary aptamer-modified Fe3O4–Au MNPs were constructed via the rapidly prepared low-temperature coincubation method (Figure B). Figure C demonstrates the detection process of the Fe3O4–Au@apt and SERS tag-based platform for S. aureus. The Fe3O4–Au@apt MNPs were introduced into the sample solution and incubated for 40 min, during which they selectively bound to S. aureus. The resulting Fe3O4–Au@apt/bacteria complexes were separated from the sample solution and subsequently conjugated with rapidly prepared SERS tags, leading to the formation of Fe3O4–Au@apt/bacteria/tags complexes. These complexes confined S. aureus at SERS hot spots, providing an amplified Raman signal and enabling sensitive detection of S. aureus.

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Schematic illustration of the SERS platform for S. aureus detection. (A) Assembly process of the aptamer/4-MBA rapidly prepared SERS tags via the low-temperature coincubation method. (B) Construction of the aptamer-modified Fe3O4–Au through the rapidly prepared method. (C) The detection process of S. aureus was performed using the rapidly prepared SERS tag-based platform. Image created in BioRender.com, with authorized permission.

3.2. Construction of the Freeze SERS Tags and Feasibility of the Biosensor

To characterize the assembly of the secondary aptamers/4-MBA cofunctionalized SERS tags, transmission electron microscopy (TEM) was employed to determine the morphology of rapidly prepared SERS tags. As illustrated in Figure A,B, in apparent contrast to the spherical and scattered appearance of AuNPs, the SERS tags exhibited a clear DNA/4-MBA layer, which proves that the preparation of the SERS tags was successful. Furthermore, UV–vis spectra and DLS were employed to confirm the formation of the secondary aptamers/4-MBA SERS tags, which were rapidly prepared using the described method. After the conjugation of the aptamer and 4-MBA, the UV–vis spectra of the rapidly prepared SERS tags showed a slight red shift (Figure C). As shown in Figure D, the AuNP diameter increased following the modification with aptamer and 4-MBA. To evaluate the stability of the freeze SERS tags, the signal intensity of the SERS tags remained relatively stable for 30 days at 4 °C (Figure E). Additionally, different concentrations of NaCl were introduced into the SERS tags. When the NaCl concentration was 0.5 M, the 4-MBA signal intensity of the freeze SERS tags remained unchanged (Figure F). The above experiments verify the successful construction of the frozen SERS tags.

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Characterization of the aptamer/4-MBA freeze SERS tags. (A,B) Representative TEM images of AuNPs (A) and SERS tags (B) (scale bars: 100 nm; scale bar in magnified image: 20 nm). (C) UV–vis spectra of AuNPs and SERS tags. (D) The DLS of AuNPs and SERS tags. (E) The Raman intensity of the freeze SERS tags after storage at 4 °C for different days. (F) The Raman intensity of the freeze SERS tags in NaCl. (G) Raman intensity of the detection of S. aureus (107 CFU/mL) with Fe3O4–Au@apt (gray), SERS tags (red), and AuNP-based traditional SERS tags (blue). (H) Raman intensity of the detection of S. aureus (106 CFU/mL) with SERS tags synthesized in different concentrations of aptamers by the cofreezing method (red) and traditional method (blue). (I) Schematic of the three different freezing modes for SERS tags and Raman signal, including the (a) preparation of the aptamer-AuNPs followed by the addition of MBA, (b) preparation of MBA–AuNPs followed by the addition of aptamer, and (c) simultaneous addition and cofreezing of MBA and aptamer to form the aptamer/MBA SERS tags.

Compared with the SERS tags prepared by traditional methods, the method we proposed has a better detection performance. The S. aureus (107 CFU/mL) was detected based on Fe3O4–Au@apt and SERS tags, and significant Raman signals were detected through the SERS platform. The Raman signals of the SERS tags we prepared are 2.28 times stronger than those of AuNP-based traditional SERS tags (Figure G). We added different concentrations of aptamers and synthesized SERS tags by cofreezing and conventional methods to obtain Raman intensity for S. aureus detection at 106 CFU/mL. In a certain concentration range, the SERS tags prepared by the cofreezing method exhibit stronger Raman signals, which may be attributed to the fact that the localization effect of the cofreezing method’s squeezing leads to more aptamers and Raman reporter molecules (MBA) binding to AuNPs (Figure H).

To further verify our hypothesis, we studied the process of SERS tag synthesis. We constructed the method of freezing aptamers and MBA with three different addition sequences: (a) preparation of aptamer-AuNPs followed by the addition of MBA, (b) preparation of MBA–AuNPs followed by the addition of the aptamers, and (c) simultaneous addition and cofreezing of MBA and aptamer to form the aptamer/MBA SERS tags. As depicted in Figure I, AuNPs maintained their pink color after a freeze–thaw cycle in modes (a) and (c), whereas in mode (b), their pink shade shifted to gray, signifying the permanent clustering of AuNPs. Despite mode (a) not causing AuNPs to aggregate, it only slightly altered Raman signals (Figure I). This may be because the aptamer occupies binding sites, preventing MBA from binding to AuNPs during stepwise freezing and causing a decrease in Raman signals. The cofreezing method (c), which adds aptamers and MBA simultaneously, allows both to be distributed reasonably and uniformly, significantly enhancing Raman signals and enabling sensitive detection (Figure I).

3.3. Characterization of the Fe3O4–Au@apt

The Fe3O4–Au was synthesized based on our prior publication. The transmission electron microscopy (TEM) demonstrated Fe3O4 and Fe3O4–Au with characteristic circular shapes. Compared to the bare Fe3O4 nanoparticle (160 nm), the diameter of these Fe3O4–Au nanoparticles expanded to 200 nm (Figure A). Energy dispersive X-ray spectroscopy (EDS) exhibited that the Au particles were dispersed uniformly on the surface of the Fe core, providing further evidence that Fe3O4–Au with a core–shell structure was successfully synthesized (Figure B). The zeta potential shifted from −17.4 mV for Fe3O4–Au to −22.3 mV following aptamer modification, indicating the successful synthesis of Fe3O4–Au@apt (Figure C). To confirm the capture efficiency of Fe3O4–Au@apt, it was mixed with different concentrations (10–104 CFU/mL) of S. aureus. After Fe3O4–Au@apt was isolated, a significant reduction in the number of remaining bacteria was observed (Figures D and S3). In contrast, Fe3O4–Au did not bind to the target bacteria, indicating that Fe3O4–Au has no affinity for the target bacteria, which illustrated the specific and high capture efficiency of Fe3O4–Au@apt targeting S. aureus.

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Evaluation of biosensor feasibility of detection. (A) TEM of Fe3O4 MNPs and Fe3O4–Au. (B) EDS mapping results of Fe3O4–Au. (C) Zeta potential of Fe3O4, Fe3O4–PEI, Fe3O4–Au, and Fe3O4–Au@apt. (D) Photographs of the colonies on blood agar plates. The number of colonies on the plate represents the number of S. aureus remaining in the supernatant of the sample after Fe3O4–Au and Fe3O4–Au@apt capture, respectively.

3.4. Optimization of the Experiment Conditions

In order to determine optimal reaction times for the capture of S. aureus by Fe3O4–Au@apt to improve the detection efficiency and accuracy, the capture rate of S. aureus at different times was determined. Figure A shows the relationship between the SERS intensity and the capture time of Fe3O4–Au@apt. About 40 min capture of Fe3O4–Au@apt was sufficient for capturing S. aureus, as shown in Figure B. The SERS signal was enhanced in parallel with the prolonged incubation time (20–60 min) of the freeze SERS tags and S. aureus; however, there was no significant increase in Raman intensity when the incubation time was varied from 50 to 60 min (Figure C,D). These findings verify that the attachment of the frozen SERS tags to S. aureus reached saturation after 50 min.

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Optimization of the experimental conditions. (A) SERS spectra for S. aureus versus the capture time of Fe3O4–Au@apt. (B) The SERS intensity of the characteristic peak of 4-MBA at 1586 cm–1 versus the capture time of Fe3O4–Au@apt. (C) SERS spectra of S. aureus versus the incubation time of the rapidly prepared SERS tags. (D) The SERS intensity of the characteristic peak of the 4-MBA peak at 1586 cm–1 is in relation to the incubation time of the rapidly prepared SERS tags. Error bars represent the standard deviation from three independent experiments.

3.5. Analytical Performance of the Proposed Platform

To confirm the analytical performance of the SERS platform based on the freeze SERS tags, different concentrations (10–107 CFU/mL) of S. aureus were prepared. The SERS intensity exhibited good linearity within the logarithmic concentration range of S. aureus (10 to 107 CFU/mL) with a LOD of 6.91 CFU/mL (Figure A,B), which is 99.25 times lower than that from AuNP-based traditional SERS tags (Figure C,D). To evaluate the selectivity of the platform, 103 CFU/mL of pathogenic bacteria including S. aureus, S. typhi, K. pneumonia, S. epidermidis, and A. baumannii was added to the platform for assaying, respectively. As shown in Figure E, S. aureus exhibited a significant and high Raman characteristic peak at 1586 cm–1, but no significant Raman characteristic peak was observed in the detection of other nontarget bacteria. To further investigate the specificity for detecting bacteria in complex samples of this platform, mixtures of S. aureus and other nontarget bacteria at a 1:10 molar ratio were tested. The Raman intensity remained consistent between S. aureus and other complex bacterial samples, showing no significant variation (Figure F). In addition, there were no significant differences in the Raman intensity of 4-MBA for S. aureus across 20 repeated experiments, with an RSD of 7.27% (Figure S2A,B). These results demonstrate that the established SERS platform has high sensitivity and specificity. Compared with other bacterial detection methods, our platform has the advantages of wider range of detection, high sensitivity, and suitable assay time for bacteria detection (Table S3).

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Analytical performance of the established SERS-based platform and AuNP-based traditional SERS tag. (A) Raman spectra of S. aureus at various concentrations ranging from 10 to 1 × 107 CFU/mL. (B) The corresponding plot of Raman intensity versus the logarithmic concentration of S. aureus was at 1586 cm–1. (C) Raman spectra of S. aureus at various concentrations ranging from 100 to 106 CFU/mL using a AuNP-based traditional SERS tag. (D) The corresponding plot of Raman intensity versus the logarithmic concentration of S. aureus at 1586 cm–1 using a AuNP-based traditional SERS tag. (E) Raman intensity of different pathogenic bacteria detected by the proposed SERS platform for evaluating the specificity of the SERS platform. (F) SERS intensity between S. aureus and other mixed bacteria samples, ten times as many other pathogens as S. aureus.

3.6. Real Sample Analysis

The ability of the proposed biosensor to detect S. aureus in different real-world samples, including human serum and urine, was carried out. Three different concentrations of S. aureus (10, 103, and 105 CFU/mL) were spiked into each of the samples and analyzed using the proposed SERS platform (Figure A). As shown in Figure S1, Fe3O4–Au@apt was highly effective at capturing S. aureus in real samples. The recovery rates for S. aureus in human serum and urine were found to range from 97.7% to 104.0% and 90.5% to 104.7%, respectively, indicating the platform’s ability to accurately measure S. aureus concentrations in real-world samples. Furthermore, we prepared sterile and S. aureus-contaminated serum and urine samples using a double-blind method and tested them with the proposed SERS platform. The results indicated that the Raman intensity of the 20 contaminated urine samples was significantly higher than that of the sterile urine samples, and a similar pattern was observed in the serum samples. These findings indicate that the method can effectively differentiate between serum and urine samples contaminated with S. aureus. Compared with other methods of S. aureus detection, our platform has the advantages of easy-preparation and high sensitivity for S. aureus detection (Table S4). Although the antibody-based methods have a shorter assay time, their cumbersome preparation, high cost, and short storage time limited their clinical application. Additionally, enzyme-based method obtains higher sensitivity. It requires longer incubation time. In summary, considering factors such as the limit of detection (LOD), assay time, and testing cost, the platform we have developed demonstrates superior advantages for rapid bacterial detection.

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Detection of S. aureus in real samples. (A) Schematic diagram of the sample analysis working principle. (B) Raman signal recovery of S. aureus spiked in urine and serum. (C,D) The Raman intensity in responding to S. aureus in urine (C) and serum (D). Image created in BioRender.com, with authorized permission.

4. Conclusions

S. aureus detection in clinical settings is crucial, owing to its ability to cause severe infections. We present a novel SERS platform that offers a rapid, sensitive, and cost-effective alternative for the detection of S. aureus. This platform integrates core–shell Fe3O4–Au@apt MNPs with freezing SERS tags, thereby addressing the key limitations of traditional detection methods and providing a more straightforward and efficient diagnostic tool. With a limit of detection of 6.91 CFU/mL, the platform demonstrates 99.25 times higher sensitivity than conventional SERS tags. This substantial enhancement can be attributed to the unique design of the Fe3O4–Au@apt MNPs and freezing SERS tags, which simplifies synthesis while improving SERS signal intensity, likely due to the stable, well-defined nanostructure generated by the efficient immobilization of aptamers and 4-MBA on AuNPs.

Successful detection of S. aureus in complex human serum and urine samples demonstrated the clinical potential of the proposed platform. The impressive recovery rates of 97.7%–104.0% and 90.5%–104.7% in serum and urine samples, respectively, were comparable to those of AuNP-based traditional SERS tags but with the added benefits of simpler preparation and improved sensitivity. , In actual sample testing, the platform effectively differentiated between sterile and S. aureus-contaminated samples, underscoring its reliability for real-world applications. The results of the study suggest that the platform could serve as a valuable tool for the rapid screening and diagnosis of S. aureus-related infections in clinical settings. However, further research is warranted to address the platform’s relatively narrow linear detection range and validate its performance in a large-scale clinical trial.

Supplementary Material

ao5c02638_si_001.pdf (391.5KB, pdf)

Acknowledgments

This research was funded by the China Postdoctoral Science Foundation (grant number: 2024M750606) and the Hight level talent project of the Affiliated Hospital of Youjiang Medical University for Nationalities (grant number: R202210302).

The data used in this study are sensitive and will not be made publicly available. The data are available from the corresponding author upon reasonable request.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c02638.

  • Detection performance of the SERS platform, comparison of the different methods and platform for the SERS platform, and sequence of aptamer used in this study (PDF)

⊥.

M.Z. and Y.X. contributed equally to this work.

All clinical serum and urine used in this study was collected from the Guangdong Provincial People’s Hospital in accordance with the institutional ethical guidelines set forth in the 1964 Declaration of Helsinki. The study was approved by the ethics committee of Guangdong Provincial People’s Hospital (S2024-954-02).

The authors declare no competing financial interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao5c02638_si_001.pdf (391.5KB, pdf)

Data Availability Statement

The data used in this study are sensitive and will not be made publicly available. The data are available from the corresponding author upon reasonable request.

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