MXene–Protein Corona Interfaces for Molecular Profiling of Alzheimer’s Disease

The protein corona (PC) that forms on the surface of nanomaterials upon contact with biological fluids provides a molecular snapshot of the host's physiological and pathological state. Here, we investigate two-dimensional (2D) titanium carbide (Ti3C2Tx) MXene nanosheets as nanobiointerfaces for capturing Alzheimer's disease (AD)-associated plasma protein signatures. Ti3C2Tx MXene flakes were incubated with plasma from clinically diagnosed AD patients and age-matched healthy controls (HC), leading to the formation of Ti3C2Tx MXene-PC complexes. Physicochemical characterization using dynamic light scattering, zeta potential analysis, and transmission electron microscopy revealed disease-dependent changes in hydrodynamic size, surface charge, and PC profile. Proteomic analysis of the isolated PC layers quantified 1,611 proteins without prior fractionation, demonstrating broad plasma proteome coverage. Principal component analysis (PCA) revealed disease-associated separation between AD and HC-derived Ti3C2Tx MXene PC proteomes along specific principal components despite interindividual heterogeneity. Differential abundance analysis identified selective enrichment of heterogeneous nuclear ribonucleoproteins (hnRNPs), annexins, and inflammatory mediators in AD-derived PC, implicating dysregulated RNA metabolism, membrane stress responses, and immune activation, hallmark processes in AD pathology. Our findings demonstrate that Ti3C2Tx MXene-PC interfaces reshape the detectable plasma proteome and enable disease-associated molecular phenotyping, establishing a versatile nanointerface-driven framework for AD-related proteomic fingerprinting and molecular profiling. These results provide a foundation for future studies exploring MXene-based biointerfaces for plasma biomarker discovery and translational diagnostic applications.