Rational Design of a Lanthanide Metal–Organic Framework as an Artificial Receptor Aptamer for Ultrasensitive Protein Sensing

Despite notable advances in molecular diagnostics, developing ultrasensitive biosensors for biomarker quantification remains a critical unmet need. Herein, we address this gap by engineering lanthanide metal–organic frameworks (Ln-MOFs) as artificial receptor aptamers (ARAs) via rational ligand design and guided optimization. Our lead Eu–TPTC Ln-MOF ([1,1′:4′,1″]-terphenyl-3,3″,5,5″-tetracarboxylic acid), optimized for maximal surface negativity, binds the cationic biomarker (cardiac troponin I, cTnI) with highly efficient electrostatic affinity. This strong affinity couples synergistically with specific target recognition to enable robust, binding-triggered signal transduction. A phosphate-mediated cascaded amplification strategy achieves a 7250-fold fluorescence enhancement and a cTnI limit of detection (LOD) of 1 pg mL–1. This performance meets clinical requirements for early diagnosis and significantly outperforms conventional ELISA in sensitivity (12.3-fold), speed, and cost-effectiveness. We establish three core ARA design principles: (i) a rigorous experimental structure–property framework linking ligand functional groups to MOF surface zeta potentials; (ii) multiscale interface engineering combining molecular docking and fluorescence assays; and (iii) an affinity-driven signal-leverage strategy. This label-free platform enables miniaturized, field-deployable diagnostics, critical for resource-limited settings. Notably, it provides a general framework for MOF-based ARAs, extends to diverse biomarkers, and lays a solid foundation for the development of highly responsive, enzyme-free biosensors for ultrasensitive biomarker quantification.