Engineering Lanthanide Metal-Organic Framework Nuclease Nanozymes: Unveiling Affinity-Driven DNA Hydrolysis

Abstract

Nuclease nanozymes promise robust, tailorable alternatives to natural nucleases, but suffer from their limited hydrolytic activity due to the Lewis acidity-centric mechanistic dogma and the unclear role of nanozyme–DNA interactions. Here, we report an affinity-driven strategy that upends conventional cognition. A series of lanthanide metal-organic frameworks (Ln-MOFs) were constructed, with catalytic efficiency decoupled from simple acid strength. Activity increased with the lanthanide atomic number despite a decrease in nanozyme-DNA affinity. Among these, Yb-BDC (terephthalic acid-based) exhibited the highest DNA-cleaving efficiency reported to date (half-life ≈ 30 min), yet showed minimal activity toward the traditional model substrate bis(4-nitrophenyl) phosphate (BNPP), thereby challenging the conventional Lewis acidity-driven paradigm. This unexpected inverse relationship reveals a critical binding-release cycle as the true driver of DNA hydrolysis. Capitalizing on this discovery, we developed a synthetic CRISPR/Cas-inspired biosensing platform by integrating Yb-BDC with rolling circle amplification, replacing natural nucleases. This system enables ultrasensitive detection of non-nucleic acid targets, expanding the scope of nanozymes in diagnostic applications. Our findings not only establish host–guest interaction engineering as a new paradigm for nuclease nanozymes design but also pioneer a modular framework for their application in biosensing technologies.

Keywords

affinity-driven DNA hydrolysis / CRISPR/Cas-inspired biosensing / Lanthanide metal-organic frameworks / nuclease nanozyme

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