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 (Ti3C2T x ) MXene nanosheets as nanobiointerfaces for capturing Alzheimer's disease (AD)-associated plasma protein signatures. Ti3C2T x MXene flakes were incubated with plasma from clinically diagnosed AD patients and age-matched healthy controls (HC), leading to the formation of Ti3C2T x 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 effective enrichment of low-abundance plasma components. Principal component analysis (PCA) revealed consistent separation between AD- and HC-derived Ti3C2T x MXene-PC proteomes despite inter-individual 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 Ti3C2T x MXene-PC interfaces act as selective molecular filters that reshape the detectable plasma proteome, enabling disease-associated molecular phenotyping and establishing a versatile nanointerface-driven framework for uncovering AD-related plasma signatures, providing a foundation for future translational diagnostic development.