Porous COF@cMOF Heterojunction‐Assisted Laser Desorption/Ionization Mass Spectrometry for Enhanced Breast‐Cancer Serum Metabolomic Screening

Abstract

ABSTRACT Early breast‐cancer (BC) screening requires reliable molecular information from minimally invasive samples, yet sensitive detection of small‐molecule metabolites in complex biofluids remains challenging. Herein, a structurally well‐defined porous heterojunction matrix, COF316@CuHHTP, is developed through an in situ epitaxial‐growth strategy for serum metabolomic screening. Porous and chemically robust COF316 serves as the core scaffold, while conductive CuHHTP forms a coherent shell for interfacial charge mediation. The resulting heterojunction enables efficient small‐molecule capture and directional transport through the channels, while enhanced photothermal conversion and optimized charge transport collectively improve desorption/ionization efficiency and sensitivity for small‐molecule metabolites. Consequently, COF316@CuHHTP enables sensitive and robust laser desorption/ionization mass spectrometry (LDI‐MS) analysis, with the maximum signal‐to‐noise (S/N) enhancement reaching ∼194‐fold, ultralow limits of detection (LODs) down to the pmol level, and strong tolerance to high‐salt and protein‐rich conditions. Applied to serum analysis, this platform enables BC diagnosis with excellent discriminatory performance (AUC = 0.996) and identifies 20 disease‐associated metabolic signatures.