Redefining Gold‐Ligand Chemistry for Biosensing: Au─C≡C Probe Enable High‐Sensitivity and Low‐False‐Positive Furin Imaging

ABSTRACT Thiolated and selenolated gold nanoparticles have been widely applied in biosensing, drug delivery, and disease diagnosis and treatment. However, under complex physiological conditions, recognition units anchored to the surface of gold nanoparticles via Au─S bonds are easily displaced by high intracellular concentrations of biothiols, leading to false‐positive signals. Au─Se bonds, on the other hand, suffer from low loading capacity and poor stability, which also hinders their performance in detection. Therefore, fundamentally resolving the instability of Au─S and Au─Se bonds and avoiding biothiol‐induced interference is of great significance for the application of gold‐based nanomaterials in biomedical fields. To address this, we designed a novel alkynyl‐modified Au─C≡C nanoplatform (Au─C≡C NPF), leveraging the superior stability of alkynyl bonds, to replace traditional Au─S NPF and Au─Se NPF. Compared with conventional systems, the Au─C≡C NPF effectively prevents signal distortion caused by intracellular biothiols, demonstrating enhanced specificity and lower detection limits in biosensing applications. It also shows excellent stability across a wide range of temperatures and pH levels, which has been further validated through theoretical calculations. This platform is easy to construct and highly feasible, offering a transformative strategy for the design of gold nanoparticle‐based probes and their application in chemical sensing and clinical diagnostics.