<i>In situ</i> partial vulcanization synthesis of a conductive and highly catalytic bimetal organic framework for sensitive electrochemical cancer-specific neoantigen detection

Neoantigens are unique tumor-derived epitopes to facilitate the development of immunotherapeutic interventions and advance the precision diagnosis of cancers. However, significant challenges remain in the detection of these neoantigens due to their inert electrochemical/fluorescent properties and low abundance, and mass spectroscopy is currently the prevailing neoantigen analysis platform, constrained by procedural complexity, prohibitive cost, and isotopic tagging. Based on <i>in situ</i> partial vulcanization synthesis of a new conductive bimetal organic framework and a peptide derivatization strategy, we demonstrate an innovative catalysis-enhanced electrochemical neoantigen biosensing platform for direct and specific electrochemical cancer diagnosis. A bimetallic sulfide nanoparticle-decorated conductive MOF nanocomposite (NiCo-MS/c-MOF) is synthesized and shows considerably enhanced electrocatalytic activity. Upon the conversion of neoantigens to electroactive molecules <i>via</i> isoindole derivatization, a significantly amplified catalytic current can be obtained on a NiCo-MS/c-MOF-modified electrode to achieve sensitive detection of the KRAS G12D neoantigen down to 0.6 nM. In addition, the monitoring of trace KRAS G12D neoantigen in complex with human leukocyte antigens on cancer cells has also been verified, highlighting the promising potential of our methodology for a precise and early diagnosis of cancers.