This study presents a sustainable strategy for the synthesis of highly defective and ultra-small tetravalent metal-organic frameworks (MOFs), specifically UiO-66(Zr) and UiO-66(Hf), with sizes around 4–6 nm and up to 35% missing linker defects. The approach involves using pre-synthesized Zr6 acetate oxoclusters and a mild green synthesis method, avoiding toxic solvents like DMF and using water and ethanol instead. The resulting nanoMOFs exhibit exceptional catalytic performance in peptide hydrolysis, showing high reactivity, selectivity, diffusion, and stability. They also demonstrate the ability to switch between hydrolysis and condensation reactions by changing the reaction solvent, enabling amide bond formation. The nanoMOFs are highly defective, with a large number of Lewis acid sites, which enhances their catalytic activity. The study also shows that these nanoMOFs are highly stable and recyclable, with excellent performance compared to other MOF catalysts. The findings suggest that these highly defective ultra-small MOFs have potential for use in heterogeneous catalysis with dual functions and improved performance. The research highlights the importance of defect engineering in MOFs for enhancing catalytic properties and opens new perspectives for the development of MOF-based catalysts.This study presents a sustainable strategy for the synthesis of highly defective and ultra-small tetravalent metal-organic frameworks (MOFs), specifically UiO-66(Zr) and UiO-66(Hf), with sizes around 4–6 nm and up to 35% missing linker defects. The approach involves using pre-synthesized Zr6 acetate oxoclusters and a mild green synthesis method, avoiding toxic solvents like DMF and using water and ethanol instead. The resulting nanoMOFs exhibit exceptional catalytic performance in peptide hydrolysis, showing high reactivity, selectivity, diffusion, and stability. They also demonstrate the ability to switch between hydrolysis and condensation reactions by changing the reaction solvent, enabling amide bond formation. The nanoMOFs are highly defective, with a large number of Lewis acid sites, which enhances their catalytic activity. The study also shows that these nanoMOFs are highly stable and recyclable, with excellent performance compared to other MOF catalysts. The findings suggest that these highly defective ultra-small MOFs have potential for use in heterogeneous catalysis with dual functions and improved performance. The research highlights the importance of defect engineering in MOFs for enhancing catalytic properties and opens new perspectives for the development of MOF-based catalysts.