Engineering Carbon Nanotube Quantum Well Defects With Recognition Tripeptides for Optical Detection of Extracellular Vesicles in Plasma

ABSTRACT Extracellular vesicles (EVs) carry surface proteins that reflect the molecular signatures of their originating cells. However, their low abundance and the modest sensitivity of current EV detection methods in complex biological environments limit access to EV surface biology in the native biological context. Here, we present a near‐infrared optical nanosensor comprising a quantum well defect functionalized carbon nanotube coupled with integrin‐recognition RGD tripeptide to detect surface integrins on EVs in a human plasma background. The nanosensor achieved sub‐picomolar detection of three integrin subunits (α5β1, αVβ1, and αVβ3) and quantified glioblastoma, ovarian cancer, and fibroblast‐derived EVs at concentrations as low as 10 4 EVs·mL −1 . Molecular dynamics simulations indicated that the RGD‐coupled quantum defect stably engages the canonical integrin‐binding pocket, localizing the binding event at the defect site and providing a structural basis for the selective response. Interestingly, the nanosensor detected comparable responses from fibroblast‐ and cancer‐derived EVs, and the finding was independently validated by surfaceome proteomics, which confirmed that RGD‐receptor integrins are present at comparable levels across all three EV populations. Our result indicates that RGD‐receptor integrins define a broadly distributed adhesion‐associated EV phenotype shared between cancer and stromal cell types, with implications for EV‐mediated tumor‐stromal interactions.