Nucleotide Driven Hierarchical Self‐Assembly of Covalent Organic Framework and Gold Nanostar for Molecular Diagnosis of Turner Syndrome

ABSTRACT Turner Syndrome (TS), a rare chromosomal disorder, cause significant phenotypical changes like growth failure and primary ovarian insufficiency. Chromosomal karyotyping, the preferred diagnostic method till date, resulting in delayed diagnosis that precludes early intervention. Hence, there is a clear unmet clinical need for rapid and cost‐effective diagnostic tool for TS. The current study focuses on developing a multiplexed molecular sensing platform that couples post‐synthetically modified, emissive COF with gold‐nanostars and gene‐specific oligonucleotides to detect TS‐associated DNA. The sensing mechanism relies on a unique self‐organization of this nucleotide decorated 2D‐COF assemblies and 3D‐gold‐nanostars in presence of their target DNA sequence. This nucleotide‐driven 2D‐3D self‐organization translates molecular recognition into convergent, trimodal readouts, i.e., fluorescence, UV–Vis, and photoacoustic scattering, from a single material construct. Responses from nineteen different rare diseased samples toward the sensor platform are compared against healthy specimens. The developed sensor has been observed to quantitatively distinguish gene‐level signatures spanning SHOX, ARSE, XIST, and VAMP7, achieving limits of detection down to 5.2–61.2 pg/mL and diagnostic accuracy up to >95% for XIST when benchmarked against gold standard methods. This programmable supramolecular assembly might have the potential to become an integral part of newborn screening programs, offering early therapeutic opportunities for TS‐affected individuals.