This study reports a sustainable strategy for the design of highly defective and ultra-small tetravalent Metal–Organic Frameworks (MOFs) (Zr, Hf) crystals (ca. 35% missing linker, 4–6 nm). Advanced characterizations reveal that these ultra-small nanoMOFs exhibit exceptional performance in peptide hydrolysis reactions, including high reactivity, selectivity, diffusion, stability, and tailorable reactivity and selectivity towards peptide bond formation by changing the reaction solvent. The ultra-small nanoMOFs show bifunctionality, as they can also catalyze the condensation reaction to form amide bonds. This work opens new perspectives for the development of heterogeneous MOF catalysts with dual functions, highlighting the importance of defect engineering and size reduction in MOFs for enhanced catalytic properties.This study reports a sustainable strategy for the design of highly defective and ultra-small tetravalent Metal–Organic Frameworks (MOFs) (Zr, Hf) crystals (ca. 35% missing linker, 4–6 nm). Advanced characterizations reveal that these ultra-small nanoMOFs exhibit exceptional performance in peptide hydrolysis reactions, including high reactivity, selectivity, diffusion, stability, and tailorable reactivity and selectivity towards peptide bond formation by changing the reaction solvent. The ultra-small nanoMOFs show bifunctionality, as they can also catalyze the condensation reaction to form amide bonds. This work opens new perspectives for the development of heterogeneous MOF catalysts with dual functions, highlighting the importance of defect engineering and size reduction in MOFs for enhanced catalytic properties.