Metal nanocluster platforms for reactive oxygen species sensing: Core-ligand design, signal transduction pathways,...

Quantitative detection of reactive oxygen species (ROS) remains challenging due to their short lifetimes, rapid interconversion, low physiological concentrations, and complex matrix effects. Metal nanoclusters (MNCs), characterized by ultrasmall dimensions, molecular-like electronic structures, and tailorable surface chemistry, have emerged as versatile platforms for ROS sensing. This review establishes a structure-mechanism-performance framework for MNC-based detection of major ROS, including H₂O₂, O₂^•-, •OH, ONOO^-, and ClO^-. Rather than cataloging materials, we critically analyze signal-transduction mechanisms beyond conventional fluorescence quenching, including electron transfer, energy-transfer processes, ratiometric responses, catalytic amplification, and oxidative core or ligand perturbation. We further evaluate how metal-core composition, ligand-shell engineering, and surface functionalization influence sensitivity, selectivity, and signal conversion. Particular attention is given to analytical challenges that hinder practical translation, including endogenous thiol interference, batch-to-batch reproducibility, photostability, calibration, and validation in complex matrices. Finally, mechanism-guided strategies are discussed for improving selectivity, quantitative reliability, and multiplexed ROS analysis.