Surface-enhanced Raman spectroscopy (SERS) fingerprinting is highly promising for identifying disease markers from complex mixtures of clinical sample, which has the capability to take medical diagnoses to the next level. Although vibrational frequency in Raman spectra is unique for each biomolecule, which can be used as fingerprint identification, it has not been considered to be used routinely for biosensing due to the fact that the Raman signal is very weak. Contemporary SERS has been demonstrated to be an excellent analytical tool for practical label-free sensing applications due its ability to enhance Raman signals by factors of up to 10⁸–10¹⁴ orders of magnitude. Although SERS was discovered more than 40 years ago, its applications are still rare outside the spectroscopy community and it is mainly due to the fact that how to control, manipulate and amplify light on the “hot spots” near the metal surface is in the infancy stage. In this Account, we describe our contribution to develop nanoachitecture based highly reproducible and ultrasensitive detection capability SERS platform via low-cost synthetic routes. Using one-dimensional (1D) carbon nanotube (CNT), two-dimensional (2D) graphene oxide (GO), and zero-dimensional (0D) plasmonic nanoparticle, 0D to 3D SERS substrates have been designed, which represent highly powerful platform for biological diagnosis. We discuss the major design criteria we have used to develop robust SERS substrate to possess high density “hot spots” with very good reproducibility. SERS enhancement factor for 3D SERS substrate is about 5 orders of magnitude higher than only plasmonic nanoparticle and more than 9 orders of magnitude higher than 2D GO. Theoretical finite-difference time-domain (FDTD) stimulation data show that the electric field enhancement |E|² can be more than 2 orders of magnitude in “hot spots”, which suggests that SERS enhancement factors can be greater than 10⁴ due to the formation of high density “hot spots” in 3D substrate. Next, we discuss the utilization of nanoachitecture based SERS substrate for ultrasensitive and selective diagnosis of infectious disease organisms such as drug resistance bacteria and mosquito-borne flavi-viruses that cause significant health problems worldwide. SERS based “whole-organism fingerprints” has been used to identify infectious disease organisms even when they are so closely related that they are difficult to distinguish. The detection capability can be as low as 10 CFU/mL for methicillin-resistant Staphylococcus aureus (MRSA) and 10 PFU/mL for Dengue virus (DENV) and West Nile virus (WNV). After that, we introduce exciting research findings by our group on the applications of nanoachitecture based SERS substrate for the capture and fingerprint detection of rotavirus from water and Alzheimer’s disease biomarkers from whole blood sample. The SERS detection limit for β-amyloid (Aβ proteins) and tau protein using 3D SERS platform is several orders of magnitude higher than the currently used technology in clinics. Finally, we highlight the promises, major challenges and prospect of nanoachitecture based SERS in biomedical diagnosis field.

This review reports recent advances in the development of long-range nanomaterial-based optical rulers.

According to the World Health Organization (WHO), multiple drug-resistant (MDR) bacterial infection is a top threat to human health. Since bacteria evolve to resist antibiotics faster than scientists can develop new classes of drugs, the development of new materials which can be used, not only for separation, but also for effective disinfection of drug resistant pathogens is urgent. Driven by this need, we report for the first time the development of a nisin antimicrobial peptide conjugated, three dimensional (3D) porous graphene oxide membrane for identification, effective separation, and complete disinfection of MDR methicillin-resistant Staphylococcus aureus (MRSA) pathogens from water. Experimental data show that due to the size differences, MRSA is captured by the porous membrane, allowing only water to pass through. SEM, TEM, and fluorescence images confirm that pathogens are captured by the membrane. RT-PCR data with colony counting indicate that almost 100% of MRSA can be removed and destroyed from the water sample using the developed membrane. Comparison of MDR killing data between nisin alone, the graphene oxide membrane and the nisin attached graphene oxide membrane demonstrate that the nisin antimicrobial peptide attached graphene oxide membrane can dramatically enhance the possibility of destroying MRSA via a synergistic effect due to the multimodal mechanism.

Circulating tumor cells (CTCs) are extremely rare cells in blood containing billions of other cells. The selective capture and identification of rare cells with sufficient sensitivity is a real challenge. Driven by this need, this manuscript reports the development of a multifunctional biocompatible graphene oxide quantum dots (GOQDs) coated, high-luminescence magnetic nanoplatform for the selective separation and diagnosis of Glypican-3 (GPC3)-expressed Hep G2 liver cancer tumor CTCs from infected blood. Experimental data show that an anti-GPC3-antibody-attached multifunctional nanoplatform can be used for selective Hep G2 hepatocellular carcinoma tumor cell separation from infected blood containing 10 tumor cells/mL of blood in a 15 mL sample. Reported data indicate that, because of an extremely high two-photon absorption cross section (40530 GM), an anti-GPC3-antibody-attached GOQDs-coated magnetic nanoplatform can be used as a two-photon luminescence platform for selective and very bright imaging of a Hep G2 tumor cell in a biological transparency window using 960 nm light. Experimental results with nontargeted GPC3(−) and SK-BR-3 breast cancer cells show that multifunctional-nanoplatform-based cell separation, followed by two-photon imaging, is highly selective for Hep G2 hepatocellular carcinoma tumor cells.

Tumor metastasis is responsible for 1 in 4 deaths in the United States. Though it has been well-documented over past two decades that circulating tumor cells (CTCs) in blood can be used as a biomarker for metastatic cancer, there are enormous challenges in capturing and identifying CTCs with sufficient sensitivity and specificity. Because of the heterogeneous expression of CTC markers, it is now well understood that a single CTC marker is insufficient to capture all CTCs from the blood. Driven by the clear need, this study reports for the first time highly efficient capture and accurate identification of multiple types of CTCs from infected blood using aptamer-modified porous graphene oxide membranes. The results demonstrate that dye-modified S6, A9, and YJ-1 aptamers attached to 20–40 μm porous garphene oxide membranes are capable of capturing multiple types of tumor cells (SKBR3 breast cancer cells, LNCaP prostate cancer cells, and SW-948 colon cancer cells) selectively and simultaneously from infected blood. Our result shows that the capture efficiency of graphene oxide membranes is ∼95% for multiple types of tumor cells; for each tumor concentration, 10 cells are present per milliliter of blood sample. The selectivity of our assay for capturing targeted tumor cells has been demonstrated using membranes without an antibody. Blood infected with different cells also has been used to demonstrate the targeted tumor cell capturing ability of aptamer-conjugated membranes. Our data also demonstrate that accurate analysis of multiple types of captured CTCs can be performed using multicolor fluorescence imaging. Aptamer-conjugated membranes reported here have good potential for the early diagnosis of diseases that are currently being detected by means of cell capture technologies.