Metal–Organic Cage as Single‐Molecule Carrier for Solid‐State Nanopore Analysis

The ability to detect biomolecules at the single‐molecule level is at the forefront of biological research, precision medicine, and early diagnosis. Recently, solid‐state nanopore sensors have emerged as a promising technique for label‐free and precise diagnosis assay. However, insufficient sensitivity and selectivity for small analytes are a great challenge for clinical diagnosis applications via solid‐state nanopores. Here, for the first time, a metal–organic cage, PCC‐57, is employed as a carrier to increase the sensitivity and selectivity of solid‐state nanopores based on the intrinsic interaction of the nanocage with biomolecules. Firstly, it is found that the carrier itself is undetectable unless bound with the target analytes and used oligonucleotides as linkers to attach PCC‐57 and target analytes. Secondly, two small analytes, oligonucleotide conjugated angiopep‐2 and polyphosphoric acid, are successfully distinguished using the molecular carrier. Finally, selectivity of nanopore detection is achieved by attaching PCC‐57 to oligonucleotide‐tailed aptamers, and the human alpha‐thrombin sample is successfully detected. It is believed that the highly designable metal–organic cage could serve as a rich carrier repository for a variety of biomolecules, facilitating single‐molecule screening of clinically relevant biomolecules based on solid‐state nanopores in the future. Metal–organic cage is used as a single‐molecule carrier for solid‐state nanopore analysis based on the intrinsic interaction of the nanocage with biomolecules. The carrier improves the sensitivity of solid‐state nanopores as demonstrated by the detection of peptides and the discrimination of two analytes that cannot be resolved without carriers. Selectivity can be easily grafted on the carrier through oligonucleotide‐tailed aptamers.