Integrating Peroxidase-like Supramolecular Crystal with Nucleic Acid Amplification Cascades for Ultrasensitive Electrochemical Detection of Mucin 1

Abstract Mucin 1 (MUC1) is an important biomarker for epithelial-derived malignancies, yet its ultratrace abundance in early tumorigenesis demands analytical methods with exceptional sensitivity. Herein, we report an ultrasensitive electrochemical aptasensing platform that integrates a biomimetic supramolecular crystal with target recycling amplification (TRA) and catalytic hairpin assembly (CHA). The supramolecular crystal (Fe-TCPP-SC) is rationally engineered by direct self-assembly of Fe(III) meso-tetra(4-carboxyphenyl)porphyrin (Fe-TCPP-(COOH)4) via hydrogen bonding, eliminating inactive metal nodes and maximizing the volumetric density of accessible peroxidase-mimicking active sites. Fe-TCPP-SC exhibits superior peroxidase-like activity and electrochemical signal amplification compared to conventional nanozymes (Fe3O4) and a representative porphyrin-based MOF (PCN-222-Fe), primarily due to its dense yet accessible iron-porphyrin motifs. By coupling Fe-TCPP-SC with TRA and CHA on a gold electrode, we developed an aptasensor translating MUC1 recognition into massively amplified electrochemical readout, with sensitivity and quantitative range outperforming most reported MUC1 assays. This aptasensor also demonstrates high specificity against common interferents (myoglobin, glucose oxidase, BSA, cholesterol, MUC2 and CA125) and excellent reproducibility (RSD = 0.89%). Furthermore, quantitative analysis of MUC1 in diluted human serum yields recoveries of 96.9-109.5%, confirming robust performance in complex biological matrices. This work establishes that hydrogen-bonded supramolecular crystals can serve as highly efficient electroactive beacons, offering a promising strategy for early cancer diagnosis.