In this work, we have reported a new general strategy for the preparation of a series of highly defective (35%-45% missing linker) and ultra-small (4-6 nm) UiO-66-based nanocrystals under fully sustainable conditions, suggesting feasibility towards upscaling. Crystal growth acts as a bottleneck in crystallization as evidenced by in situ TD-DLS with ex situ HRTEM/STEM and can be manipulated by simply using additional solvent. Missing linker defects have been assessed by multiple advanced techniques, including PXRD, FTIR, TGA, HRTEM and in situ FTIR spectroscopy coupled with CD3CN probe, which revealed the importance of Lewis-acidity of the HD-US-UiO-66. The resulting HD-US-UiO-66-X showed excellent catalytic performance in both peptide bond hydrolysis and formation with very remarkable catalytic reactivity, selectivity, product recovery efficiency, and recyclability compared to other reported materials. Detailed investigation of the influence of defects, particle size and functionalization on the catalytic activity of the nanoMOFs provided unique insights into the key parameters that influence the reactivity, and as such demonstrate how nanoMOFs can be tuned to show specific and selective reactivity through precise control of catalysts' properties. Therefore, the discoveries reported here might further promote the development of nanoMOFs as heterogeneous catalysts having dual functions and performance enhancements in varying aspects. Furthermore, the novel materials presented here may be also used for the development of sensing/optical devices (preliminary results in SI, Figure ), membranes, nanomedicine formulations and to explore other fundamental size-dependent properties.