Tingting Zheng

Surface-enhanced Raman spectroscopy (SERS) is an optical ultrasensitive analytical method, which provides special chemical fingerprints and enables noninvasive identification of trace biological species. Traditional noble-metal SERS substrates often require surface engineering to mitigate nonspecific adsorption and background interference in complex biological matrices. Recently, semiconductors have demonstrated great potential as a complementary route, where weaker nonspecific adsorption and energy-level-matched charge transfer-based enhancement can yield highly selective readouts. Unfortunately, low enhancement performance limits their practical applications for trace analysis. Here, we report a Ga-doped ZnO superlattice SERS substrate exhibiting a record-high free carrier density of 9.23 × 10²¹ cm^-3 among semiconductors as well as a remarkable SERS performance factor on par with noble metals. The exceptional Raman enhancement arises from unique characteristics of atomic-level alternating interfaces, enabling effective charge separation and a novel light-induced hot electron transfer pathway. Notably, self-trapped states induced by strong electron-phonon coupling inherent to superlattices further facilitate charge separation and magnify SERS signals. We subsequently integrate this substrate into an ultrafast culture-free SERS platform for the simultaneous identification of five ventilator-associated pneumonia (VAP) pathogens with a detection limit of 1.0 CFU/mL, exhibiting 100% accuracy involving 50 hospitalized patients suspected of VAP. Significantly, the total detection time is reduced from more than 48-72 h to 10 min, and the per-test cost is estimated down to US$0.15. To our knowledge, this is the first report of Raman enhancement based on semiconductor superlattice, which offers a promising strategy for multiplex screening of biological species, paving the way for next-generation point-of-care diagnostic technologies.

Dental caries, endodontic infections, and periodontitis are the predominant bacterial diseases that damage oral tissues and even exacerbate systemic disorders. Given the limited efficacy of traditional disinfectants, the current staged approach to dental treatment often fails to achieve a complete cure, frequently necessitating repeated interventions and exposing patients to a high risk of recurrence. Therefore, the development of a highly effective antimicrobial strategy is of great significance for the treatment of oral infectious diseases. Here, we report a multifunctional hybrid nanozyme, referred to as PB@MoS₂@Au, consisting of a Prussian blue (PB) nanocube core decorated with a molybdenum disulfide (MoS₂) shell and further functionalized with gold nanoparticles (AuNPs). This nanozyme integrates enhanced peroxidase-like activity and a high photothermal conversion efficiency of 37.4% within the mild-hyperthermia window (≈50 °C). The combined treatment of PB@MoS₂@Au, low-concentration hydrogen peroxide (H₂O₂, 200 μM), and near-infrared (NIR) irradiation exhibited potent antibacterial efficacy against seven representative oral bacterial strains, achieving bactericidal rates as high as 95%. Furthermore, this treatment effectively eradicated bacteria within biofilms, with killing rates exceeding 90%. Most importantly, in an ex vivo tooth infection model, this combined treatment eliminated over 99.5% of Enterococcus faecalis biofilms from root canals within minutes. This remarkable antibacterial performance is primarily attributed to the photothermally enhanced catalytic generation of reactive oxygen species (ROS) by PB@MoS₂@Au, together with its direct photothermal effect, which leads to bacterial cell membrane disruption, intracellular content leakage, and glutathione (GSH) depletion, ultimately resulting in bacterial death. Moreover, the system demonstrated favorable biocompatibility and achieved therapeutic efficacy in a rat model of apical periodontitis without inducing significant systemic toxicity. This work demonstrates the promising application potential of the PB@MoS₂@Au-based combined treatment in oral antimicrobial therapy, particularly for root canal infection control.

This Perspective commemorates 50 years of surface-enhanced Raman scattering (SERS) by highlighting the paradigm shift toward rationally designed semiconductor substrates, enabling ultrasensitive and molecule-selective detection. Several enhancement strategies have been developed to effectively modulate the electronic band structure and charge transfer (CT) processes, such as energy level customization, amorphization, quasi-metallization, and morphology control, achieving high enhancement factors with good selectivity and stability. Moreover, semiconductor SERS substrates show broad prospects in the fields of bio-sensing and cancer diagnosis. Nevertheless, standardization gaps in substrate reproducibility and data comparability hinder its widespread adoption. Resolving these challenges through multi-stakeholder collaboration is essential to bridge the technology transfer gap and establish SERS as a core platform for next-generation inspection.

Periodontitis, which owns a significant prevalence rate, is a chronic inflammatory disorder caused by the infection of multiple microorganisms. Porphyromonas gingivalis (P. gingivalis) serves as a key pathogenic biomarker for periodontitis. However, currently, there is a lack of diagnostic tools that are able to quickly and precisely quantify levels of P. gingivalis. Therefore, developing a quantitative detection method for this pathogenic bacterium is critical for the diagnosis and management of this disease. Herein, based on the petal-like spherical ZnO@ZIF-8 composite substrate, we built an innovative semiconductor surface-enhanced Raman spectroscopic (SERS) platform specifically engineered for the detection of P. gingivalis with high speed, sensitivity, and stability. The detection of P. gingivalis on this SERS platform takes only 30 min. It also has excellent long-term stability for over 60 days. This platform exhibits an extensive linear range from 4 × 103 CFU/mL to 4 × 108 CFU/mL, while also owning a low limit of detection (LOD) of 38 CFU/mL for P. gingivalis. The developed method provides a novel pathway for precise diagnosis and efficient screening of periodontitis, and explores new directions for detecting other disease-related biomolecules, including proteins, small molecules, peptides, and miRNAs at the same time.

Perovskites have recently emerged as attractive optoelectronic semiconductors due to tunable bandgap, large absorption coefficient, and long carrier lifetime, making it ideal as a kind of chemical‐mechanism based surface‐enhanced Raman scattering (SERS) substrates. However, perovskites generally demonstrate poor stability at ambient conditions, limiting their applications for SERS bioanalysis. Herein, we created a perovskite‐based heterostructure through effectively passivating defects at the interface with hydrophobic organic semiconductors, which simultaneously enhanced the stability and efficiency of perovskite SERS substrate. The significant enhancement factor of 10 ⁷ was mainly stemmed from the resonance Raman effect and the highly‐efficient charge transfer process driven by a novel light‐induced hot electron transfer mechanism in plasmon‐free substrates previously never reported. This system was subsequently developed as an integrated theranostic SERS platform for miR‐146a monitoring with a detection limit down to 0.2 fM, successfully guiding the early theranostics to enhance the therapeutic efficiency for Alzheimer's disease (AD). This work brings new light into the design of efficient and stable semiconductor SERS substrate and opens novel diagnosis and treatment options for AD.

Perovskites have recently emerged as attractive optoelectronic semiconductors due to tunable bandgap, large absorption coefficient, and long carrier lifetime, making it ideal as a kind of chemical‐mechanism based surface‐enhanced Raman scattering (SERS) substrates. However, perovskites generally demonstrate poor stability at ambient conditions, limiting their applications for SERS bioanalysis. Herein, we created a perovskite‐based heterostructure through effectively passivating defects at the interface with hydrophobic organic semiconductors, which simultaneously enhanced the stability and efficiency of perovskite SERS substrate. The significant enhancement factor of 10 ⁷ was mainly stemmed from the resonance Raman effect and the highly‐efficient charge transfer process driven by a novel light‐induced hot electron transfer mechanism in plasmon‐free substrates previously never reported. This system was subsequently developed as an integrated theranostic SERS platform for miR‐146a monitoring with a detection limit down to 0.2 fM, successfully guiding the early theranostics to enhance the therapeutic efficiency for Alzheimer's disease (AD). This work brings new light into the design of efficient and stable semiconductor SERS substrate and opens novel diagnosis and treatment options for AD.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder globally, progressively impairs patients' cognitive functions and their ability to perform daily living activities.

Mental stress is a dangerous factor for the health of living beings, which can lead to various diseases. However, currently, there is a lack of diagnostic tools that can quickly and accurately quantify levels of mental stress. Cortisol is an important stress hormone that is widely present in bodily fluids; its concentration can reflect the level of mental stress in organisms. Here, we report a surface-enhanced Raman spectroscopy (SERS) probe based on flower-like graphene oxide-molybdenum disulfide composite material functionalized with cortisol DNA recognition element and tetracyanoquinodimethane of Raman label, with a remarkable enhancement factor value of 7.38 × 10⁵, which exhibits excellent cortisol detection ability in a wide range of concentrations from 1 nM to 1 000 nM, with the limit of detection down to 0.773 nM. The whole detection takes only 20 min. In addition, the SERS probe can selectively detect cortisol in other substances with similar chemical structures, which makes the probe applicable to complex biological systems with good reproducibility and stability. This designed SERS probe has been successfully employed in the detection of mouse serum cortisol, with high accuracy compared with enzyme-linked immunosorbent assay (ELISA) results, demonstrating great potential in actual biological sample detection.

Accumulating evidence supports an important role of phospholipase D3 (PLD3) in the pathogenesis of Alzheimer's disease (AD), while the actual expression level and distribution of PLD3 remains controversial in AD. Developing specific nanoprobes could be a promising strategy to understand PLD3 better, but there are limited approaches available in this field for a simple, reliable, and biocompatible biosensor. In this work, we report a PLD3-induced fluorescence resonance energy transfer (FRET) nanoprobe utilizing tetrahedral DNA nanostructures (TDNs) for visualizing the fluctuation of PLD3 at organ and subcellular levels in AD. Hydrolysis of PLD3 to a specific nucleotide strand on TDN will turn the FRET probe to an OFF state, which results in changes in fluorescent intensity. Immunofluorescent staining of brain sections proved the reliability of TDN nanoprobe to visualize PLD3 and the upregulation of PLD3 was observed in AD mice. Subsequent application of the nanoprobe uncovered PLD3 in the heart tissue of AD mice for the first time. Further investigations on the cellular level revealed a good colocalization of TDN nanoprobes with lysosomes in normal neurons, while their fluorescent signal overlaps better with mitochondria than lysosomes in AD neurons. Our finding provides not only insights into PLD3 but also an inspiring application of TDNs in the mechanism research of AD at multiple levels.