Customized Controllable Pyrophosphate Nanosensor Based on Lanthanide Metal–Organic Frameworks for Accurate and Sensitive Detection of Nucleic Acids

Pyrophosphate (PPi) and nucleic acid amplification play a critical role in medical diagnostics, making the development of precise nanosensors essential. Lanthanide metal-organic frameworks (Ln-MOFs) are increasingly recognized for their potential in advanced luminescent biosensing applications. However, research on customized controllable responses in Ln-MOF nanosensors is still lacking, which is critical for the molecular-level modular design. In this work, we introduce a ligand engineering strategy to regulate coordination-induced antenna effect emission in Ln-MOFs, optimizing their pyrophosphate (PPi) sensing from fluorescence turn-off to turn-on modes. By tuning the coordination environment through ligand programming, we discovered a "near coordination compensation" effect, allowing for controllable transitions between aggregation-induced emission and quenching (AIE/AIQ). This reversible response was supported by density functional theory calculations. Using a Eu³⁺/Tb³⁺ dual-emission Ln-MOF designed with 2,6-pyridinedicarboxylic acid as the optimized ligand, we developed a self-correcting PPi nanosensor with a detection limit of 0.2 μM. Moreover, this system enabled ultrasensitive nucleic acid detection, achieving a limit of detection (LOD) as low as 1 fM, with applications in DNA pyrosequencing, qPCR, and DNA epigenetic modification (5-formylcytosine) analysis. These findings shed light on the structural and photophysical factors controlling Ln-MOF luminescence, offering a promising platform for highly accurate and sensitive nucleic acid detection in biomedical diagnostics.