Nanomaterial-Assisted Physical Mass Loading and Signal Amplification Strategies for Exosome Isolation and Sensing in Liquid Biopsy: A Review.

Exosomes and small extracellular vesicles are promising liquid-biopsy biomarkers because they carry molecular information from their cells of origin and can be accessed from minimally invasive biofluids. Reliable separation and detection are made more difficult by their small size, low abundance, diverse composition, and co-occurrence with lipoproteins, protein aggregates, and other extracellular particles. To improve exosome enrichment, capture, and sensing, nanomaterial-assisted techniques have become crucial. Using a mechanism-based approach that differentiates between non-gravimetric signal amplification and genuine physical mass loading, this study offers an organized comparison of nanomaterial-enabled exosome sensing techniques. This distinction is helpful because different transducers measure different physical quantities: while optical, electrochemical, fluorescent, catalytic, and nucleic acid-based platforms typically benefit from enhanced signal generation rather than increased mass, resonant and gravimetric sensors benefit from increased inertial or surface-bound mass. In terms of amplification mechanism, transducer compatibility, sample-matrix tolerance, workflow complexity, and translational maturity, the review contrasts metallic nanoparticles, magnetic systems, metal-organic frameworks, carbon and two-dimensional materials, quantum dots, upconversion nanomaterials, DNA nanostructures, and polymer-based platforms. The gap between analytical sensitivity and clinical utility, including separation purity, recovery, biological heterogeneity, pre-analytical variability, interference from complex biofluids, and the need for uniform validation, is given special focus. The review concludes that no single nanomaterial or amplification method is universally optimal; instead, platform-aware, application-specific integration of isolation, amplification, and validation techniques is necessary for clinically meaningful exosome sensing.