Over the past few decades, the development of colloidal nanocrystals has led to a revolution in material science due to their very appealing properties in heterogeneous catalysis, optics, biology, and engineering. Indeed, most nanomaterials undergo dramatic changes in their properties when their particle size lies in the ultra-small scale (e.g. below 5-10 nm) such as the quantum size effect in semiconductor materials, catalytic properties for inert noble metals, or electrical conductivity for insulators. Metal-organic frameworks nanocrystals (nanoMOFs) are porous solids assembled from metal ions/oxoclusters and organic linkers. The reduction of the MOFs size to the nanoscale has imparted nanoMOFs with various enhanced properties (i.e., catalysis, sensing, biomedicine…) and novel features, but despite advances, the design of ultra-small MOF nanoparticles still faces severe difficulties. This can be due either to the much larger unit-cell parameters of MOFs in comparison with inorganic nanomaterials and/or to the limited chemical stability of targeted nanoMOFs. However, at this ultra-small size, the majority of the atoms of MOFs lie close to the external surface, which maximizes the interface for substrate interaction alongside largely decreases diffusion/desorption path length, naturally resulting in enhanced catalytic properties. Defect engineering is a long term interest in crystalline nanomaterials, particularly due to the influence of vacant sites on catalysis. Interestingly, structural defects in MOFs have shown similar optimizations towards catalytic properties and/or gas separation. However, this is in most cases associated with a lower chemical stability due to the reduction of metal-ligand connectivity and/or the presence of additional accessible metal sites. UiO-66(Zr) or Zr6O4(OH)4(BDC)6 (BDC= Benzene-1,4-dicarboxylic acid) is a prototypical zirconium-based MOF with a very high thermal and chemical stability due to its high connectivity (12-connected mode) and robust Zr-carboxylate bonds. Consequently, defect engineering in MOFs has been to date mainly focused on UiO-66(Zr) and its derivatives. The most typical method for the defect engineering in Zr-MOFs is the modulator-induced-defect approach (MIDA), where a monocarboxylate modulator (formate, acetate…) is added, binding preferentially with metal centers in place of the linker, leading to the missing ligand vacancy defects. As such, the defect content can be controlled by the amount of the modulator used. Figure . Scheme of a) the conventional modulator-induced-defect approach (MIDA) for the size-defect tuning of MOFs, b) the new approach that produces ultra-small and highly defective Zr-MOFs nanoparticles.