Membrane-free coacervates, typically formed through electrostatic interactions between oppositely charged polyelectrolytes, have been extensively utilized as artificial life-like systems in protocell research, providing valuable insights into the origin of life. However, considering that inorganic metal ions may have been more abundant under early Earth conditions, it is plausible that these metal ions played a significant role in prebiotic compartmentalization. In this study, we present a novel coacervate protocell formed via liquid-liquid phase separation (LLPS) of simple anionic polypeptides, induced by electrostatic and coordination interactions with inorganic metal cations, using divalent zinc ions as a specific example due to their prebiotic availability and biological relevance. The peptide-zinc ion coacervate microdroplet exhibits liquid-like properties, client partitioning, and enhanced catalysis comparable to those of typical polyelectrolyte coacervates. By integrating experimental results and theoretical simulations, we identify two kinetic pathways to phase separation mediated by the coordination mode at varying zinc ion concentrations, resulting in the formation of nonequilibrium gel-like condensates or droplets that further contribute to distinct light-induced catalytic efficiency. Overall, our work highlights that peptide-metal ion interaction-driven compartmentalization, as prebiotic microreactors, could have facilitated primitive biochemical reactions on early Earth, thus offering a plausible and diverse pathway for the emergence of protocells.

Synchronously regulating the electronic structures of metal and nonmetal sites offers a promising approach for developing highly active electrocatalysts, yet it has not been applied to the construction of advanced lithium–sulfur battery (LSB) electrocatalysts, and the related optimization mechanisms have not been fully explored. Herein, a highly active LSB electrocatalyst of Ni-Co3Se4 with superior performance was developed by synchronously regulating the electronic structures of Co and Se atoms in MOF-derived mixed-valence Co3Se4 nanomaterials. The synchronous shift of the d-band center of Co and the p-band center of Se toward the Fermi level, along with the increase in total electron density at the Fermi level, enables Ni-Co3Se4 to adsorb sulfur species more efficaciously and catalyze their redox conversion more efficiently. The LSBs incorporating Ni-Co3Se4 deliver a high initial discharge capacity (1462 mAh g−1), along with excellent rate performance (4.0C, 743 mAh g−1) and outstanding cycling stability. Even under lean-electrolyte conditions, the batteries with a sulfur loading of 6.77 mg cm−2 still sustain a discharge capacity of 755 mAh g−1 after 70 cycles. This work demonstrates the significant effectiveness of synchronously regulating the electronic structures of metal and nonmetal sites in optimizing LSB electrocatalysts and reveals the corresponding mechanism.

Exploring the metabolic kinetics mediated by cytochrome P450 (CYP) enzymes is essential for understanding pharmacokinetic and toxicological mechanisms. However, real-time monitoring of CYP-mediated enzymatic reactions remains challenging for conventional techniques. Here, we report the first attempt to develop a surface-enhanced Raman scattering (SERS)-based analytical platform for the direct, real-time tracking of enzymatic metabolism and extraction of critical kinetic parameters. An in vitro CYP enzyme system was constructed to emulate hepatic microsomal activity, using pyrene (Pyr) as a model and polycyclic aromatic hydrocarbon (PAH) as the model substrate. Cetyltrimethylammonium bromide (CTAB)-induced Ag aggregates enabled simultaneous detection of Pyr (408 cm-1) and its metabolite 1-hydroxypyrene (1-OHPyr; 426/617 cm-1) directly within the reaction medium. The hydrophobic CTAB self-assembled monolayer enhanced analyte enrichment and suppressed protein interference, while the intrinsic Raman band of CTAB at 760 cm-1 served as a reliable internal standard for quantitative kinetic assessment. This platform allowed real-time monitoring of CYP-catalyzed oxidation of Pyr, yielding pseudo-first-order kinetics (k = 0.00501 min-1) and the Michaelis constant Km of 13 μM. Furthermore, inhibition studies identified CYP1A2 as the principal isoform responsible for Pyr metabolism, corroborated by the potent inhibitory activity of α-naphthoflavone (with calculated IC50). To our knowledge, this work represents the first instance of SERS for time-resolved monitoring of CYP-mediated metabolism, expanding its capability from static detection to dynamic biochemical analysis. The proposed strategy provides a simple, label-free, and time-resolved approach for enzyme kinetic studies, inhibitor screening, and metabolic analysis.

Metabolites serve as crucial carriers of both physiological and pathological information, making their quantitative detection significant for disease diagnosis and the evaluation of metabolic status. Hydrogen peroxide (H2O2), a byproduct of enzymatic reactions related to metabolites, can act as an indirect indicator of changes in metabolite concentrations. In this study, we present a coacervate microdroplet-based surface-enhanced Raman spectroscopy (SERS) sensor that facilitates the accurate quantification of metabolites involving H2O2. This sensor is readily prepared by co-encapsulating unmodified gold nanoparticles (AuNPs), H2O2-responsive 3-mercaptophenylboronic acid (3-MPBA), and specific oxidases. Following the optimization of the amounts of encapsulated AuNPs, the optimized sensor achieves excellent performance for H2O2 detection, with a limit of detection (LOD) of 1.38 & times; 10-9 M, exhibiting high specificity and reproducibility. As a proof of concept for metabolite detection, we applied this platform to sense glucose and uric acid following in situ enzymatic reactions, achieving LODs of 7.54 & times; 10-9 M and 1.47 & times; 10-9 M, respectively, with linear responses range from 10-5 to 10-9 M. Furthermore, recovery experiments in diluted urine showed recovery rates of 99.61%-102.66% for glucose and 98.02%-102.65% for uric acid, both with RSD less than 5%, confirming the stability, accuracy, and applicability in complex biological matrices. Consequently, this plasmonic coacervate SERS sensor serves as a novel, rapid, and sensitive platform for the direct quantification of metabolites involved in H2O2. By simply substituting the encapsulated oxidase, this strategy can be readily extended to a wide array of clinically relevant targets, thereby holding significant potential for early disease diagnosis.

Conventional benzimidazole synthesis faces several challenges, including harsh reaction conditions, the formation of aldehyde-related byproducts, and a lack of comprehensive mechanistic insights. To address these limitations, we engineered a bifunctional Cu/ZnO catalyst that facilitates high-efficiency synthesis of benzimidazole while enabling in situ mechanistic monitoring. The spherical ZnO superstructure enhances Lewis acidity (91.2 µmol g-1) optimizing the adsorption of o-arylenediamines. Concurrently, Cu nanoparticles (NPs) promote charge separation, evidenced by a 6-fold increase in photocurrent and a carrier lifetime of 1.57 ns, while selectively cleaving the α-C─H bonds of alcohols to generate •CH(R2)OH radicals such as •CH(CH3)OH. Notably, this radical-driven pathway circumvents the formation of aldehyde intermediates, achieving a record 2-methylbenzimidazole (2MBZ) productivity of 3.28 mmol g-1 h-1 with a yield of 98% yield and over 95% stability across five cycles. Furthermore, integrated surface-enhanced Raman scattering (SERS) spectroscopy provides detailed insights at the single-particle level, directly capturing transient species, such as radical intermediates (1170 cm-1) and Schiff bases (1568 cm-1). These findings elucidate the dual role of Cu NPs in both radical adsorption/cross-coupling and Lewis acid-mediated stabilization of intermediates. Thus, this work establishes a synergistic strategy that combines high-efficiency photocatalysis with in situ mechanistic tracking for sustainable heterocycle synthesis.

Rapid and reliable discrimination of structurally similar small molecules in complex systems remains a significant challenge for chemical sensing, particularly when subtle structural variations lead to highly overlapping spectral features. Herein, we develop a semiconductor surface-enhanced Raman scattering (SERS) platform based on ZnO superstructures for the reliable discrimination of structurally similar flavonoids in both single-component and multicomponent systems. The ZnO-based SERS platform enables the generation of molecule-specific spectral fingerprints, with characteristic variations in both skeletal vibration and functional group regions, allowing effective differentiation of closely related flavonoids. By integrating multivariate statistical analysis, robust classification, and discrimination of flavonoids with highly similar structures were achieved, including in mixed-component systems. The practical applicability of the platform is further validated using real plant-derived samples, where distinct spectral signatures enable effective discrimination of samples with different compositional profiles, thereby demonstrating its capability for botanical origin authentication. Notably, the proposed approach allows rapid analysis with minimal sample pretreatment and without the need for chromatographic separation. These results demonstrate that ZnO-based semiconductor SERS sensing provides a robust and scalable strategy for the detection and discrimination of structurally similar flavonoids in complex systems, highlighting its practical applicability for quality control and authenticity assessment in food and plant-derived materials.

Sustaining high-energy hot carriers in plasmonic metals remains a central challenge for multi-electron photocatalytic transformations due to rapid hot-carrier recombination. Here, we demonstrate that crystal-facet engineering of semiconductor supports provides an effective strategy to regulate interfacial electron-hole compensation in plasmonic heterostructures. By constructing Au nanoparticles on SnO2 nanooctahedra dominantly exposing either {111} or {332} facets, we reveal that the {332} facet promotes more efficient interfacial electron injection into plasmonically excited Au, enabling effective compensation of hot holes and thereby sustaining the hot-electron population. In situ surface-enhanced Raman scattering (SERS) spectroscopy, kinetic analysis, and photoelectron spectroscopy collectively show that Au-SnO2{332} drives the complete six-electron reduction of 4-nitrothiophenol under near-infrared excitation with a rate constant 6.6 times higher than that of Au-SnO2{111}. Power- and wavelength-dependent studies further confirm that the enhanced activity originates from facet-governed hot-carrier dynamics rather than photothermal or direct semiconductor excitation effects. Energy-level alignment analysis indicates that the {332} facet provides more favorable energetics for electron transfer to neutralize plasmon-generated hot holes, thereby mitigating recombination losses. These findings establish interfacial electron-hole compensation as a decisive parameter in plasmonic multi-electron catalysis and identify crystal facet engineering as a general design principle for sustaining hot carriers in metal-semiconductor nanostructures.

Abnormal lactic acid (LA) enantiomeric excess (ee) in biofluids is closely associated with various intestinal diseases. Here, we report a chiral-label-free nonplasmonic surface-enhanced Raman scattering (SERS) platform using a ZIF-8/ZnS heterojunction that enables direct quantification of LA enantiomers and their ee values in raw human urine through a charge-transfer-driven chiral recognition mechanism. Our findings indicate that an enantioselective hydrogen bonding between 4-mercaptopyridine (4-MPy) probes and LA enantiomers induces differential charge-transfer effects within the ZIF-8/ZnS@4-MPy system, evidenced by the selective enhancement of specific vibrational modes in the SERS spectra of 4-MPy and enantiomer-specific changes in the fluorescence lifetime of ZnS. This innovative system integrates signal amplification and stereoselectivity without the use of noble metals or chiral modifiers, overcoming critical limitations associated with the complexity of preparing chiral plasmonic substrates. The platform achieves ultrasensitive detection limits (10 nM), linear response to ee values (R2 = 0.98), high measurement precision (RSD < 8.28%, n = 20), long-term stability (28-day), and clinical-grade accuracy against enzymatic assays (RMSEP = 1.97). This work presents an efficient, noninvasive method for the analysis of chiral metabolites in urine, while establishing a novel direction for plasmon-free SERS chiral sensing.

Reliable quantification of structurally similar flavonoids in complex matrices remains challenging due to spectral overlap and matrix interference. Here, we report a semiconductor surface-enhanced Raman scattering (SERS) sensing platform based on an interface-engineered N-doped anatase/rutile TiO2 phase junction that enables multiplex quantification through a charge-transfer enhancement mechanism. The engineered interface synergistically modulates the electronic structure, facilitating efficient charge-transfer resonance under 785 nm excitation and thereby improving Raman sensitivity. The optimized platform enables quantitative detection of representative flavonoids with limits down to 5 & times; 10-6 M, which are much below the typical concentration levels of flavonoids in nutraceuticals, and exhibits good signal reproducibility. To resolve overlapping spectral features in multicomponent systems, partial least-squares regression is integrated with SERS, enabling accurate multiplex quantification of structurally similar flavonoids in complex mixtures. The sensing strategy is further validated using crude extracts of Scutellaria baicalensis, where the quantified compositions show strong agreement with liquid chromatography-mass spectrometry results, demonstrating robustness in real-world samples with minimal pretreatment. This work establishes an interface-engineered semiconductor SERS platform for multiplex chemical sensing and highlights its potential for rapid analysis in complex natural systems.

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.

Biomolecular condensates formed by liquid-liquid phase separation (LLPS) play a crucial role in organizing biochemical processes within living cells. The phase transition of these condensates from a functional liquid-like state to a pathological gel-like or solid-like state is believed to be linked to cellular dysfunction and various diseases. Here, we present a biomimetic model to demonstrate that endogenous enzyme-catalyzed crosslinking within condensate-mimicked coacervate microdroplets can promote a liquid-to-gel phase transition. We identify the transformation in physical characteristics of the densely packed microdroplets including reduced internal mobility, increased storage modulus, selective blocking of large nanoparticles, and enhanced salt resistance. The reversible dynamics of gel-like microdroplets mediated by ionic strength exhibited a limited release and recapture of sequestered positively charged guest molecules. Furthermore, we validate that the phase transition contributes to a restricted biochemical process through an enzymatic cascade. Overall, this work represents an adaptive in vitro platform for exploring the phase transitions associated with the physiological functions of biomolecular condensates and offers chemical insights and perspectives for investigating potential mechanisms involved in phase transitions.

As the emergence of prototissues promotes the evolutionary transformations of protolife, tissue-like networks derived from cytomimetic systems have been studied by using artificial cells as building blocks to mimic prototissues at a higher organizational level. However, liquid-like networks originating from liquid-liquid phase separation (LLPS), especially heterogeneous LLPS, are less reported. Herein, we report a binary liquid droplet-based protocell network composed of coacervates and aqueous two-phase systems (ATPS) droplets arranged in an alternating sequence, integrating both associative and segregative LLPS. This network with worm-like chains can be specifically achieved only when the attached droplets are partially engulfed, mediated by the interfacial tension between coacervate and ATPS droplets. Notably, the interconnected droplets within the network are capable of spatially self-sorting of biomacromolecules into separate domains, thereby facilitating biomacromolecular extraction and biological reactions within designated droplets. Upon changes in the external environment, the network can be reconfigured to enable morphological regulation of trienzymatic cascade reactions. Overall, this work highlights that an all-aqueous network, coupling both associative and segregative LLPS, can be engineered as a possible route toward a hybrid prototissue-like system, offering new insights into the design of higher-ordered biomimetic systems utilizing liquid soft matter.

The persistent accumulation of micro-nanoplastics (MnPs) in aquatic environments poses serious ecological and health risks, but their efficient removal and detection remain challenging due to their diverse compositions and sizes. Here, we design a highly hydrophobic magnetic nanoplatform (Fe3O4@PDA-HDTMS, F@PH), characterized by low surface energy and multi-interaction adsorption, to effectively integrate multiple functions, including enrichment, removal, detection, and quantification of MnPs. The optimized platform effectively captured polyethylene (PE), polypropylene (PP), and polystyrene (PS) MnPs, achieving removal efficiencies of 93.8% for microplastics (MPs) and 87.2% for nanoplastics (NPs) in ultrapure water. It also maintained high performance in complex matrices, including tap water (84.3-85.8%), simulated seawater (73.2-76.3%), and tissue suspensions (67.8-71.0%). Coupled with a photoinduced microbubble-enhanced SERS (PMERS) platform strategy, F@PH generates microbubbles and thermocapillary flow, promoting the enrichment of MnPs onto silver nanoparticle (AgNP) substrates, which results in a 102-fold signal enhancement compared to conventional SERS, allowing for ultrasensitive detection of MnPs. The detection limits reach 5 μg mL-1 and 10 μg mL-1 for 500 nm PE and PP MnPs, respectively. This integrated platform demonstrates high sensitivity and applicability in the analysis of bottled water and biological tissues, offering a promising approach for precise monitoring of MnPs and environmental remediation.

Metalloporphyrins have been extensively employed as model systems for mimicking heme enzymes and single-site catalysts. Understanding their catalytic mechanism at the molecular level, especially through in situ/operando characterization is of significant interest. Herein, we report the synthesis of bifunctional Ag@porphyrin core@shell nanocomposites (NCs) using Ag nanocubes and iron meso-tetra(4-carboxyphenyl) porphyrin (FeTCPP) via a facile noncovalent self-assembly method. The synthesized Ag@FeTCPP NCs inherit the advantages of ferric porphyrin regarding multienzyme-mimicking properties, while exhibiting exceptional surface-enhanced Raman scattering (SERS) activity. Using the disproportionation reaction of hydrogen peroxide as an example, single-nanoparticle SERS analysis of Ag@FeTCPP NCs facilitates the operando characterization of reactive intermediates involved in porphyrin-based catalytic cycles. In conjunction with the density functional theory (DFT) calculation and isotopic labeling experiment, three key intermediate species of ferric-hydroperoxo (FeIII-OOH), ferryl-oxo porphyrin radical cation (Por+•-FeIV═O), and ferryl-hydroxy (FeIV-OH) are clearly identified through dynamic SERS spectra. These results for the first time link spectroscopic characteristics to the theoretically expected water-assisted proton-coupled electron transfer mechanism. This work not only presents an efficient SERS model for exploring the nature and evolution of unstable reactive intermediates involved in porphyrin-associated catalytic systems, but also offers a generalizable design strategy for the fabrication of a novel iron-porphyrin catalyst.

Exposing unsaturated sites by modulating the lattice ordering is very efficacious in optimizing the catalytic performance of catalytic materials. Paracrystalline materials, which are intermediate between amorphous and crystalline materials, integrate some of the excellent properties of both and are rich in atomically ordered-disordered intersections with unsaturated sites. These characteristics enable paracrystalline materials to demonstrate potentially superior catalytic activity that efficiently facilitates the redox conversion of lithium polysulfides (LiPSs). However, paracrystalline materials have not been applied to improve the electrochemical performance of lithium-sulfur (Li-S) batteries, and the modulation mechanism by which their unique paracrystalline features affect the adsorption and catalytic performance of electrocatalysts for LiPSs remains unrevealed. Herein, a paracrystalline Co3O4 hollow flower-shaped sphere (PC-Co3O4 HFS) was engineered and employed as an efficient electrocatalyst for Li-S batteries. By modulation of the formation of the ordered-disordered intersections within the PC-Co3O4 HFS, numerous oxygen vacancies and active sites were created. This enables the PC-Co3O4 HFS to exhibit robust adsorption and catalytic capabilities, thereby effectively anchoring LiPSs and significantly accelerating the redox kinetics of sulfur species. Moreover, the Li+ transport behavior is also significantly improved by the PC-Co3O4 HFS. The batteries employing the PC-Co3O4 HFS exhibited a high discharge capacity of 818.74 mA h g-1 at 4.0 C and retained a capacity of 545.06 mA h g-1 after 500 cycles at 2.0 C, demonstrated excellent rate performance and cycling stability. Even at a high sulfur loading of 13.4 mg cm-2, the batteries with the PC-Co3O4 HFS delivered an impressive areal capacity of 10.49 mA h cm-2. This study successfully demonstrates the ability of paracrystalline materials to enhance the electrochemical performance of Li-S batteries, deepening the comprehending of the lattice ordering degree effect in Li-S electrochemistry.

Noncovalent interactions (NCIs) are crucial for biological bond-forming events and have significant applications across various branches of chemistry. Here, we demonstrate for the first time the identification of multiple NCIs between two interacting species using semiconductor-based surface-enhanced Raman scattering (SERS) spectroscopy. This was accomplished by designing submicrometer-sized TiO2 superstructures with synergistic effects of Mie and charge-transfer resonances for SERS enhancement, enabling the TiO2/4-mercaptobenzoic acid (MBA) system to achieve both high SERS activity and interfacial charge-transfer sensitivity. The results clearly indicate that the vibrational frequencies of MBA shift in correlation with various intermolecular interactions from hydrogen-bonding to ionic interactions. Multiple SERS analyses of NCIs were conducted for both the four DNA bases and single-stranded DNA sequences. Additionally, we performed a proof-of-concept study utilizing the relative SERS intensity to detect the relative content of two bases in single-stranded DNA sequences. This study unlocks potential applications of semiconductor SERS for exploring intermolecular-specific interactions.

The spontaneous emergence of Turing patterns in biological systems has inspired advanced materials with superior performance, yet their untapped potential in surface‐enhanced Raman spectroscopy (SERS) technology offers a transformative frontier. Mirroring the anti‐reflective coating of insect eyes, where Turing‐patterned corneal protrusions form graded refractive index interfaces with the lens, a bioinspired integration of Turing‐nanoarchitected Ag (TN‐Ag) with in situ zeolitic imidazolate framework‐8 (ZIF‐8) growth is engineered. The electrochemically sculpted fractal framework on silver needles serves dual roles as plasmonic amplifiers and curvature‐guided templates for ZIF‐8 growth, spatially aligning electromagnetic hotspots with selective‐enrichment porous channels. The TN‐Ag/ZIF‐8 hierarchical architecture enables dual‐scale SERS enhancement through mesoscopic light modulation via refractive index gradients and microscopic molecular enrichment through size‐selective pores. Leveraging 4‐mercaptophenylboronic acid as a dual‐recognition probe, this platform achieves ultrasensitive discrimination and detection of Hg 2+ (10 −10 m ) and methylmercury (10 −8 m ) with exceptional interference resistance and practical reliability. Further, its injector‐integrated design permits direct sampling in untreated solid matrices while seamlessly interfacing with portable Raman systems, demonstrating readiness for real‐world environmental monitoring and food safety diagnostics. By transmuting biomimetic principles into functional nanofabrication, this work establishes a universal paradigm for next‐generation on‐site chemical analysis, uniting biological design logic with engineered sensing demands.

The year 2024 marks the 50th anniversary of the discovery of surface-enhanced Raman spectroscopy (SERS). Over recent years, SERS has experienced rapid development and became a critical tool in biomedicine with its unparalleled sensitivity and molecular specificity. This review summarizes the advancements and challenges in SERS substrates, nanotags, instrumentation, and spectral analysis for biomedical applications. We highlight the key developments in colloidal and solid SERS substrates, with an emphasis on surface chemistry, hotspot design, and 3D hydrogel plasmonic architectures. Additionally, we introduce recent innovations in SERS nanotags, including those with interior gaps, orthogonal Raman reporters, and near-infrared-II-responsive properties, along with biomimetic coatings. Emerging technologies such as optical tweezers, plasmonic nanopores, and wearable sensors have expanded SERS capabilities for single-cell and single-molecule analysis. Advances in spectral analysis, including signal digitalization, denoising, and deep learning algorithms, have improved the quantification of complex biological data. Finally, this review discusses SERS biomedical applications in nucleic acid detection, protein characterization, metabolite analysis, single-cell monitoring, and in vivo deep Raman spectroscopy, emphasizing its potential for liquid biopsy, metabolic phenotyping, and extracellular vesicle diagnostics. The review concludes with a perspective on clinical translation of SERS, addressing commercialization potentials and the challenges in deep tissue in vivo sensing and imaging.