面向去中心化脓毒症诊断的结构可调智能纳米酶

《TRAC-TRENDS IN ANALYTICAL CHEMISTRY》：Structurally Tunable Smart Nanozymes toward Decentralized Sepsis Diagnosis

　　

## Introduction

Sepsis remains a major global health burden requiring rapid diagnosis within a narrow clinical decision window, with mortality increasing by approximately 7.6% for every hour of delay in appropriate antimicrobial therapy [1], [2], [3]. In clinical practice, the rate of missed or delayed sepsis diagnosis ranges from 8.2% to 20.8% because its signs and symptoms substantially overlap with those of other inflammatory and infectious conditions [4]. Biomarkers play a critical role in sepsis diagnosis by facilitating early disease detection and monitoring. Several biomarkers associated with sepsis pathophysiology have been investigated, including lipopolysaccharide (LPS), procalcitonin (PCT), interleukin-6 (IL-6), C-reactive protein (CRP), lactate, thrombin, cardiac troponin I (cTnI), aspartate transaminase (AST), alanine transaminase (ALT), and microRNAs (miRNAs). However, detecting and quantifying them in biofluids is analytically challenging because of their diverse physicochemical and biological characteristics and distinct sensing requirements [5], [6], [7], [8], [9], [10]. Moreover, many of these biomarkers are not specific to sepsis, and standardized clinical decision thresholds remain insufficiently established, further complicating their interpretation in diagnosis. For example, a relatively low IL-6 cutoff of 52.6 pg mL?1 has been reported in septic patients, differing by only 2.48 pg mL?1 from the corresponding value reported in trauma patients [11], [12]. miRNAs represent another emerging class of biomarkers, but their clinical translation remains limited by low abundance, extraction challenges, high sequence homology, and a lack of standardized quantification methods and clinically validated cutoff values [6], [10], [13]. Further analytical and clinical validation is therefore required to establish the suitability of such biomarkers for routine sepsis diagnosis.

Conventional laboratory methods, including blood culture and polymerase chain reaction (PCR) for pathogen detection, as well as enzyme-linked immunosorbent assays (ELISA) and chemiluminescent immunoassays for biomarker quantification, remain important for sepsis diagnosis but often involve lengthy analysis and multistep procedures [1], [14], [15]. The resulting demand for the rapid, decentralized detection of sepsis-associated biomarkers has stimulated the development of portable biosensing platforms [16], [17], [18]. For instance, a label-free, needle-shaped microelectrode immunosensor has been developed for rapid, real-time electrochemical detection of IL-6, achieving physiologically relevant detection levels with short incubation times and demonstrating potential for point-of-care (POC) and continuous intravascular sepsis monitoring [19]. However, this platform relies on antibody-functionalized gold microelectrodes for electrochemical detection without catalytic signal amplification. To enhance signal generation, several biosensors have incorporated natural enzymes, such as alkaline phosphatase (ALP) or horseradish peroxidase (HRP), as catalytic labels for detecting sepsis-associated pathogens and PCT; however, their performance can be constrained by assay time, sensitivity, enzyme stability, and storage requirements [15], [20]. These limitations have motivated the integration of engineered nanomaterials with high specific surface areas, favorable electron-transfer properties, tunable optical and electrical characteristics, and versatile surface chemistry to enhance signal generation and analytical performance [21], [22], [23], [24]. Integrating such nanomaterials into established sensing modalities, including electrochemical and surface-enhanced Raman scattering (SERS) platforms, can further improve signal amplification, analytical sensitivity, and overall detection performance [17], [24], [25], [26].

Among the functional nanomaterials developed for biosensing [26], [27], [28], nanozymes are particularly attractive because they combine the physicochemical properties of nanomaterials with intrinsic enzyme-mimicking catalytic activity [29], [30]. This dual functionality enables nanozymes to act as both signal transducers and catalytic signal amplifiers, converting molecular recognition events into amplified analytical signals and thereby improving detection sensitivity [30], [31]. Beyond catalytic amplification, nanozyme-based nanostructures can also serve as carriers, conductive interfaces, enrichment elements, plasmonic components, or immobilization scaffolds, facilitating their integration into optical, electrochemical, and multimodal sensing platforms [22], [28]. Recent reviews have summarized nanozyme synthesis, catalytic mechanisms, and applications in biosensing and analytical platforms for disease diagnosis and biomarker detection [21], [29], [31], [32], [33], [34], [35], [36], [37], [38]. In contrast, this review focuses on engineering nanozyme structure and dimensionality as key determinants of catalytic activity and signal transduction, thereby establishing dimension-dependent structure–activity–sensing relationships for sepsis biomarker detection with improved sensitivity, dynamic range, and analytical performance in clinical samples. A representative example is a two-dimensional (2D) MXene/AuAg nanoparticles (NPs) nanozyme platform, in which a conductive, electroactive MXene framework is integrated with AuAg NPs to promote electron transfer and signal amplification for the ultrasensitive detection of sepsis-associated exosomal miR-125b. Subsequent integration with machine-learning algorithms enabled diagnostic classification based on the biomarker-derived signals, allowing discrimination among patients with sepsis, patients with general inflammation, and healthy individuals [39].

This review focuses on translating dimensional nanozymes into analytical strategies for sepsis diagnosis, where reliable biomarker detection is complicated by low target abundance, limited specificity, and variable levels of clinical validation. As illustrated in Fig. 1, we establish a structure–activity–sensing framework that links zero-dimensional (0D) to three-dimensional (3D) architectures to sepsis biomarker requirements, enzyme-like catalysis, signal-generation mechanisms, and decentralized sensing platforms. Beyond single-mode sensing, particular attention is given to dual-mode sensing, portable paper-based lateral flow immunoassays (LFIA), wearable biosensors, and artificial intelligence (AI)-driven nanozyme biosensors that can improve the reliability and information content of sepsis-related biomarker measurements. Although nanozyme-based biosensors have been extensively developed, their application to sepsis detection remains relatively underexplored. Therefore, dimension-engineered nanozyme biosensors targeting sepsis-related biomarkers are evaluated to explore their potential implementation in future sepsis diagnostic platforms. Finally, we critically discuss the remaining challenges associated with sepsis biomarkers, nanozyme reproducibility, catalytic standardization, multiplex integration, and clinical translation, and outline future opportunities for developing sensitive, portable, and intelligent nanozyme-based platforms for decentralized sepsis diagnosis.

## Section snippets

**Nanozyme catalysis: from material structure to analytical signal generation**

Nanozymes have emerged as versatile catalytic materials because their enzyme-like activity can be modulated through nanoscale structural and compositional engineering [30], [31]. Unlike natural enzymes, whose catalytic functions are governed by defined three-dimensional protein structures and active-site microenvironments, nanozyme catalysis arises from surface and interfacial active sites whose properties are influenced by defects, coordination environments, electronic structure, and nanoscale [features].

**Representative sepsis biomarkers and analytical challenges**

The Sequential Organ Failure Assessment (SOFA) score is widely used to assess organ dysfunction in sepsis and is associated with disease severity and mortality risk [90]. However, because SOFA primarily reflects established organ dysfunction, its ability to detect early pathophysiological changes preceding overt organ injury is inherently limited. Early sepsis involves molecular and cellular alterations that can precede clinically detectable organ dysfunction, creating a critical window for [early intervention].

**Linking dimensional nanozyme architectures to biosensors for sepsis biomarker detection**

The analytical performance of nanozyme-based biosensors is fundamentally governed by the interplay among structural architecture, catalytic behavior, and signal transduction [31]. Because sepsis biomarkers differ markedly in molecular structure, circulating abundance, temporal kinetics, and clinical decision thresholds, no single nanozyme architecture is universally optimal for all biosensing applications. Instead, nanozyme dimensionality plays a critical role in governing active-site [accessibility and reactivity].

**Advanced strategies for next-generation nanozyme-based biosensing platforms**

Dimensional engineering establishes the catalytic and structural advantages of nanozymes, whereas their analytical performance in biosensing is further determined by their integration into advanced sensing platforms through rational functionalization. In complex biological sample analysis, such as sepsis diagnostics, high catalytic activity alone is often insufficient for reliable biomarker detection because challenges related to target specificity, matrix interference, and multiplexed analysis [remain significant].

**Challenges and future perspectives**

Nanozymes are attractive signal-transduction components for sepsis-oriented biosensing because their intrinsic enzyme-like catalytic activity can amplify signals arising from biomolecular recognition events, while their structurally tunable physicochemical properties facilitate integration with diverse optical and electrochemical sensing modalities. In this review, we presented nanozyme-enabled sepsis biosensing from a dimension-dependent perspective (0D–3D), emphasizing how nanozyme [structure dictates analytical performance].

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## CRediT authorship contribution statement

**Hye Jin Lee:** Writing – review & editing, Supervision, Resources, Project administration, Funding acquisition.
**Huynh Minh Thao Hua:** Writing – review & editing, Writing – original draft, Visualization, Investigation, Data curation, Conceptualization.
**Mungyeong Jeong:** Writing – review & editing, Software, Data curation.
**Yeonjoo Son:** Writing – review & editing, Writing – original draft, Software, Investigation, Data curation, Conceptualization.
**Chelladurai Karuppiah:** Writing – review & editing.

## Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Data Availability

Data will be made available on request.

## Declaration of Competing Interest

? The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgments

This project was supported by the National Research Foundation of Korea (NRF) grant, funded by the Korean government (Ministry of Science and ICT, MSIT) (Grant number: RS-2024-00343620). It was also partially supported by the Regional Innovation System & Education (RISE) Glocal University 30 project through the Daegu RISE Center, funded by the Ministry of Education and the Daegu City (2025-RISE-03-001 to C. Karuppiah).

**Huynh Minh Thao Hua | Yeonjoo Son | Mungyeong Jeong | Chelladurai Karuppiah | Hye Jin Lee**