Metal-Organic Framework as a Bioorthogonal Catalyst for Gene Editing.

We report the use of reticular design to construct metal-organic frameworks (MOFs) with molecularly defined catalytic pores for bioorthogonal RNA manipulation in living cells. A library of crystalline MOFs with systematically varied Cu cluster geometries, pore dimensions, and chemical environments was assembled to interrogate how structural precision influences RNA recognition and conversion within confined spaces. By integration of redox-stable Cu(I) clusters with dimensionally matched mesopores, selected MOFs were capable of catalyzing efficient and quantitative RNA bond cleavage and formation reactions in living systems without external reducing agents. Small-angle X-ray scattering reveals that pore chemistry governs substrate positioning relative to catalytic centers, enabling preferential engagement of protected RNA and facilitated release of original RNA as products, thereby driving complete conversion. Synchrotron soft X-ray microscopy was used to visualize intracellular localization and integrity of MOF in cells, further validating MOF as a bioorthogonal catalyst. An amine-functionalized framework, MOF-248-NH2, enabled controlled sgRNA activation for CRISPR/Cas9 gene editing regulation in cells and treatment of cardiac disease in a canine model. These results establish reticular pore engineering as a powerful strategy to make MOFs programmable bioorthogonal catalysts.