Surface-enhanced Raman spectroscopy (SERS) has evolved significantly over fifty years into a powerful analytical technique. This review aims to achieve five main goals. (1) Providing a comprehensive history of SERS's discovery, its experimental and theoretical foundations, its connections to advances in nanoscience and plasmonics, and highlighting collective contributions of key pioneers. (2) Classifying four pivotal phases from the view of innovative methodologies in the fifty-year progression: initial development (mid-1970s to mid-1980s), downturn (mid-1980s to mid-1990s), nano-driven transformation (mid-1990s to mid-2010s), and recent boom (mid-2010s onwards). (3) Illuminating the entire journey and framework of SERS and its family members such as tip-enhanced Raman spectroscopy (TERS) and shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) and highlighting the trajectory. (4) Emphasizing the importance of innovative methods to overcome developmental bottlenecks, thereby expanding the material, morphology, and molecule generalities to leverage SERS as a versatile technique for broad applications. (5) Extracting the invaluable spirit of groundbreaking discovery and perseverant innovations from the pioneers and trailblazers. These key inspirations include proactively embracing and leveraging emerging scientific technologies, fostering interdisciplinary cooperation to transform the impossible into reality, and persistently searching to break bottlenecks even during low-tide periods, as luck is what happens when preparation meets opportunity.

Surface-enhanced Raman spectroscopy (SERS) has evolved significantly over fifty years into a powerful analytical technique. This review aims to achieve five main goals. (1) Providing a comprehensive history of SERS's discovery, its experimental and theoretical foundations, its connections to advances in nanoscience and plasmonics, and highlighting collective contributions of key pioneers. (2) Classifying four pivotal phases from the view of innovative methodologies in the fifty-year progression: initial development (mid-1970s to mid-1980s), downturn (mid-1980s to mid-1990s), nano-driven transformation (mid-1990s to mid-2010s), and recent boom (mid-2010s onwards). (3) Illuminating the entire journey and framework of SERS and its family members such as tip-enhanced Raman spectroscopy (TERS) and shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) and highlighting the trajectory. (4) Emphasizing the importance of innovative methods to overcome developmental bottlenecks, thereby expanding the material, morphology, and molecule generalities to leverage SERS as a versatile technique for broad applications. (5) Extracting the invaluable spirit of groundbreaking discovery and perseverant innovations from the pioneers and trailblazers. These key inspirations include proactively embracing and leveraging emerging scientific technologies, fostering interdisciplinary cooperation to transform the impossible into reality, and persistently searching to break bottlenecks even during low-tide periods, as luck is what happens when preparation meets opportunity.

Abstract Lysosomes are critical in modulating the progression and metastasis for various cancers. There is currently an unmet need for lysosomal alkalizers that can selectively and safely alter the pH and inhibit the function of cancer lysosomes. Here an effective, selective, and safe lysosomal alkalizer is reported that can inhibit autophagy and suppress tumors in mice. The lysosomal alkalizer consists of an iron oxide core that generates hydroxyl radicals (•OH) in the presence of excessive H + and hydrogen peroxide inside cancer lysosomes and cerium oxide satellites that capture and convert •OH into hydroxide ions. Alkalized lysosomes, which display impaired enzyme activity and autophagy, lead to cancer cell apoptosis. It is shown that the alkalizer effectively inhibits both local and systemic tumor growth and metastasis in mice. This work demonstrates that the intrinsic properties of nanoparticles can be harnessed to build effective lysosomal alkalizers that are both selective and safe.

Metal nanoparticles, especially when synthesized on a large scale, often exhibit significant heterogeneity in size and shape, which can limit their reliability and reproducibility in various applications, including plasmonics. This study introduces a centrifugal depletion-induced flocculation (CDF) method for the scalable and efficient purification of Au nanocubes (AuNCs). Unlike traditional flocculation methods, CDF leverages controlled centrifugation and depletion interactions to achieve high particle homogeneity and recovery efficiency while significantly reducing processing time. Systematic optimization of critical parameters, such as nanoparticle concentration, centrifugal force, and flocculation time, enabled recovery efficiency exceeding 98% and yields of approximately 98–99% for 60 nm AuNCs. The adaptability of this method was also demonstrated for NCs of varying sizes and larger volumes, underscoring its versatility and scalability for diverse nanoparticle systems. The superior monodispersity and shape uniformity of purified AuNCs achieved through this approach hold significant potential for applications requiring precise control over plasmonic properties, such as high-performance optical sensors and integrated nanophotonic systems.

Analyzing the cell interface is of paramount importance in understanding how cells interact and communicate with other cells, but an advanced analytical platform that can process complex and networked interactions between cell surface ligands and receptors is lacking. Herein, we developed the cell-interface-deciphering lipid nanotablet (CID-LNT) for multiplexed real-time cell analysis. LNT is a nanoparticle-tethered lipid bilayer chip where freely diffusing plasmonic nanoparticles induce scattering signal changes. The CID-LNT transduces cell surface protein information into DNA data, which operate as nanoparticle logic gates. As a proof of concept, we detected and analyzed programmed death-ligand 1 (PD-L1) and associated immune signals (TNF-α, EGF, and IFN-γ). PD-L1 is an immune checkpoint that suppresses T cell activity with inflammatory biomolecules facilitating its expression. The CID-LNT can serve as a dynamic nanoparticle logic board, enabling the logic gate-based analysis of membrane proteins, and can be expanded to immunological synapse analysis, cell interface engineering, and molecular diagnostics.

The spatial configuration of molecules on metal surfaces is a key parameter in reliably modulating the surface-enhanced Raman scattering (SERS) signals quantitatively, but the methods and platforms for controlling this configuration are not well established. Here, we utilized metal-organic frameworks (MOFs) to periodically and spatially arrange molecules in synthesizing zeolite imidazole framework-8 (ZIF-8)/Au core/shell nanocubes (ZACS NCs) for quantitative SERS. The uniform plasmonic Au nanoshell deposition onto ZIF-8 NCs was accomplished by the (100) facets of ZIF-8 and the use of cetyltrimethylammonium chloride (CTAC). In ZACS NCs, an interfacial Au/Zn alloy layer is between the AuNC core and ZIF-8 shell, which can modulate the plasmonic properties of the ZACS NCs. Single-particle Raman analysis suggests that characteristic vibrational Raman moieties of 2-methylimidazole (2-mIM) ligands have a clear laser polarization angle dependence. Importantly, the micro-Raman analysis results from all of the eight different vibrational moieties of ZIF-8 display highly linear relationships between particle concentration and SERS intensity, verifying that the spatially aligned configuration and periodicity of these moieties within ZIF-8 generate quantitative SERS signals. Finally, it was shown that the characteristic Raman peaks of 2-mIM ligands from the ZACS NCs can be used to detect and differentiate various targets of interest. This opens a new paradigm for versatile plasmonic porous materials.

ConspectusThe preserved bosonic nature of surface plasmon polaritons from incident photons allows plasmonic nanomaterials to serve as effective photonic platforms. The strong light–matter interaction occurring at the surface concentrates light energy within a narrow region, thereby altering the local density of optical states. This modified photonic environment is typically expressed as near-field enhancement and improves the transition probability of nearby molecules or quantum emitters. However, despite the potential of plasmonic nanostructures to act as signal-transducers, issues in generating reproducible and consistent photonic responses with these platforms hinder their wide use for practical applications. As the parameters of plasmonic modulation are highly sensitive to even minor differences in surface morphology, a key origin of fluctuation in optical responses is the physical heterogeneity of the constituent nanostructures themselves. Therefore, although statistical and analytical techniques can obtain optically consistent signals from plasmonic nanostructures, the necessity of synthesizing uniform plasmonic nanostructures to achieve identical optical signals is becoming ever-more evident.This Account focuses on synthetic approaches to ensure structural uniformity of plasmonic nanostructures, which in turn produces precisely tunable and reproducible optical signals. The discussion begins with methods to realize monodispersity in simple forms of plasmonic nanostructures whose geometric homogeneity can be acquired during the nucleation and growth stages of synthesis. As heterogeneous nanoparticles of different shapes and their corresponding nonuniform plasmonic responses originate primarily from differences in seed crystallinity, nucleation─the point at which the crystallinity of the nanoparticle emerges─plays a crucial role. By gaining an understanding of how reduction rate, surface ligands, and etching control the formation of seeds with different crystallographic structures, strategies for obtaining homogeneous seed structures are explained. This is followed by discussions about the growth stage where the final morphology of nanostructures is determined. The main task of this subsequent growth stage is the preservation of initial crystallinity by balancing the interplay between deposition and surface diffusion. Lastly, shape-selective purification strategies are investigated, particularly depletion-induced flocculation, as they remove impurities and improve overall yields.Meanwhile, the advanced functionality of plasmonic nanostructures has been achieved through the synthesis of more complex architectures. Accordingly, this Account then discusses approaches using the monodisperse basic nanostructures as building blocks, either by acting as templates on which secondary structures can be grown or by their self-assembly into multidimensional superlattices. Template synthesis maintains the uniformity of initial structures while endowing nanostructures with enhanced functionality via compositional or structural complexity. In addition, the assembly of building blocks into superlattices can strengthen their optical responses via coupling between constituent plasmonic nanostructures. The degree of coupling is correlated to their interparticle distance and spatial orientation, reinforcing the necessity of uniform plasmonic nanostructures beyond the particle level. In closing, we examine how the uniformity of the synthesis is reflected in plasmonic platforms by investigating representative case studies, involving plasmonic scattering and photoluminescence signals. By evaluating plasmonic nanostructures based on their uniformity, we address the current need for standardization toward widespread use and imminent commercialization of plasmonic platforms and highlight their importance in practical applications.

<div class="section abstract"><div class="htmlview paragraph">For mature virtual development, enlarging coverage of performances and driving conditions comparable with physical prototype is important. The subjective evaluation on various driving conditions to find abnormal or nonlinear phenomena as well as objective evaluation becomes indispensable even in virtual development stage. From the previous research, the road noise had been successfully predicted and replayed from the synthesis of system models. In this study, model based NVH simulator dedicated to virtual development have been implemented. At first, in addition to road noise, motor noise was predicted from experimental models such as blocked force and transfer function of motor, mount and body according to various vehicle conditions such as speed and torque. Next, to convert driver’s inputs such as acceleration and brake pedal, mode selection button and steering wheel to vehicle’s driving conditions, 1-D performance model was generated and calibrated. Finally, the audio and visual feedback correspondent with driver’s input was represented in the simulator with real-time data network between various hardware and software. To validate the simulator, subjective evaluation was performed with so-called virtual vehicles by changing tires, rubber mounts, suspension and body on various roads, speed and torque, which showed contextual results with physical prototypes. In conclusion, the NVH simulator equipped with consistent experimental and simulation models could be utilized to find and improve abnormal or nonlinear phenomena in virtual vehicle development stage, which can help to frontload vehicle development.</div></div>

Surface-enhanced Raman scattering has been widely used for molecular/material characterization and chemical and biological sensing and imaging applications. In particular, plasmonic nanogap-enhanced Raman scattering (NERS) is based on the highly localized electric field formed within the nanogap between closely spaced metallic surfaces to more strongly amplify Raman signals than the cases with molecules on metal surfaces. Nanoparticle-based NERS offers extraordinarily strong Raman signals and a plethora of opportunities in sensing, imaging and many different types of biomedical applications. Despite its potential, several challenges still remain for NERS to be widely useful in real-world applications. This Perspective introduces various plasmonic nanogap configurations with nanoparticles, discusses key advances and critical challenges while addressing possible misunderstandings in this field, and provides future directions for NERS to generate stronger, more uniform, and stable signals over a large number of structures for practical applications.