Understanding carboxyl–metal ligand interaction has great significance in analytical chemistry. Herein, we use resonant surface-enhanced Raman scattering (SERS) to probe the physiochemical interaction and conformation change in several metal ion–carboxyl coordination complex systems adsorbed on the surface of plasmonically resonant metal nanostructures. Our SERS results and density function theory calculations jointly reveal that low-valence metal ions (such as K+ and Pb2+) tend to bind to the carboxyl active site of a Raman tag molecule, 4-mercaptobenzoic acid (4-MBA), in a unidentate binding mode of low binding energy whereas high-valence metal ions (such as Fe3+) favor a bidentate binding mode of relatively high binding energy. Particularly, Pb2+-ion concentration-dependent SERS suggests a repulsive interaction among the coordination complex leading to a tilted configuration of 4-MBA on the metal surface. This work indicates the resonant SERS approach is suitable not only for studying the carboxyl–metal ligand interaction but also for detecting various types of heavy metal ions at low concentrations.

Surface-enhanced Raman scattering (SERS)-based biosensors are promising tools for virus nucleic acid detection. However, it remains challenging for SERS-based biosensors using a sandwiching strategy to detect long-chain nucleic acids such as nucleocapsid (N) gene of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because the extension of the coupling distance (CD) between the two tethered metallic nanostructures weakens electric field and SERS signals. Herein, we report a magnetic-responsive substrate consisting of heteoronanostructures that controls the CD for ultrasensitive and highly selective detection of the N gene of SARS-CoV-2. Significantly, our findings show that this platform reversibly shortens the CD and enhances SERS signals with a 10-fold increase in the detection limit from 1 fM to 100 aM, compared to those without magnetic modulation. The optical simulation that emulates the CD shortening process confirms the CD-dependent electric field strength and further supports the experimental results. Our study provides new insights into designing a stimuli-responsive SERS-based platform with tunable hot spots for long-chain nucleic acid detection.

NPs) with unique optical properties have emerged as one of the most exciting tools in nanomedicine, capable of achieving multiple tasks such as optical imaging, [2] targeted chemotherapy, [3] and localized photothermal therapy (PTT), [4][5][6] for efficient tumor theragnostics and preventing tumor recurrence. Prior to the therapy, the solid tumor can be spatially visualized by NP-based imaging techniques for precise diagnosis. Among various NPenhanced imaging technologies, surfaceenhanced Raman spectroscopy (SERS) has exhibited great potential for ultrasensitive biological imaging with advantages of low-cost, non-ionizing excitation light, the unique vibrational spectrum, ultra-narrow spectral line-width, high resistance to photo bleaching, and high signal-to-noise ratio. [7,8] Especially, it has been employed for tracking the biodistribution of injected NPs in vivo systems. For instance, Campbell et al. used Raman imaging to evaluate the biodistribution and clearance kinetics of plamonic NPs together with other techniques, including positron emission tomography (microPET), hyperspectral imaging, and inductively coupled plasma mass spectrometry (ICP-MS) over 48 h post-ingestion, [9] suggesting the reliability of translating high-sensitivity Raman contrast imaging into clinical practice. Therefore, there is high demand for developing strong NP-constructed SERS tags that show great prospects for effective optical guidance of tumor identification and imaging. Surface-enhanced Raman scattering (SERS) imaging has emerged as a promising tool for guided cancer diagnosis and synergistic therapies, such as combined chemotherapy and photothermal therapy (chemo-PTT). Yet, existing therapeutic agents often suffer from low SERS sensitivity, insufficient photothermal conversion, or/and limited drug loading capacity. Herein, a multifunctional theragnostic nanoplatform consisting of mesoporous silicacoated gold nanostar with a cyclic Arg-Gly-Asp (RGD)-coated gold nanocluster shell (named RGD-pAS@AuNC) is reported that exhibits multiple "hot spots" for pronouncedly enhanced SERS signals and improved nearinfrared (NIR)-induced photothermal conversion efficiency (85.5%), with a large capacity for high doxorubicin (DOX) loading efficiency (34.1%, named RGD/DOX-pAS@AuNC) and effective NIR-triggered DOX release. This nanoplatform shows excellent performance in xenograft tumor model of HeLa cell targeting, negligible cytotoxicity, and good stability both in vitro and in vivo. By SERS imaging, the optimal temporal distribution of injected RGD/ DOX-pAS@AuNCs at the tumor site is identified for NIR-triggered local chemo-PTT toward the tumor, achieving ultraeffective therapy in tumor cells and tumor-bearing mouse model with 5 min of NIR irradiation (0.5 W cm −2 ). This work offers a promising approach to employing SERS imaging for effective noninvasive tumor treatment by on-site triggered chemo-PTT.

Background: CRISPR-Cas12a has been integrated with nanomaterial-based optical techniques, such as surface-enhanced Raman scattering (SERS), to formulate a powerful amplification-free nucleic acid detection system. However, nanomaterials impose steric hindrance to limit the accessibility of CRISPR-Cas12a to the narrow gaps (SERS hot spots) among nanoparticles (NPs) for producing a significant change in signals after nucleic acid detection. Methods: To overcome this restriction, we specifically design chimeric DNA/RNA hairpins (displacers) that can be destabilized by activated CRISPR-Cas12a in the presence of target DNA, liberating excessive RNA that can disintegrate a core-satellite nanocluster via toehold-mediated strand displacement for orchestrating a promising "on-off" nucleic acid biosensor. The core-satellite nanocluster comprises a large gold nanoparticle (AuNP) core surrounded by small AuNPs with Raman tags via DNA hybridization as an ultrabright Raman reporter, and its disassembly leads to a drastic decrease of SERS intensity as signal readouts. We further introduce a magnetic core to the large AuNPs that can facilitate their separation from the disassembled nanostructures to suppress the background for improving detection sensitivity. Results: As a proof-of-concept study, our findings showed that the application of displacers was more effective in decreasing the SERS intensity of the system and attained a better limit of detection (LOD, 10 aM) than that by directly using activated CRISPR-Cas12a, with high selectivity and stability for nucleic acid detection. Introducing magnetic-responsive functionality to our system further improves the LOD to 1 aM. Conclusion: Our work not only offers a platform to sensitively and selectively probe nucleic acids without pre-amplification but also provides new insights into the design of the CRISPR-Cas12a/SERS integrated system to resolve the steric hindrance of nanomaterials for constructing biosensors.

Chemo/Photothermal Therapy for Cancer Guided by SERS Imaging In article number 2206762, Mo Yang, Siu Hong Dexter Wong, and co‐workers develop a multilayered mesoporous gold nanoarchitecture labeled with Raman reporters for ultraeffective surface‐enhanced Raman scattering (SERS) imaging‐guided synergistic therapy toward cancer. This nanoplatform enables efficient xenograft tumor model targeting with sensitive SERS imaging in vitro and in vivo for identifying the tumor cells and optimal therapeutic time point, thereby achieving the highest therapeutic outcome of noninvasive near‐infrared triggered photothermal therapy and hyperthermia enhanced chemotherapy.