Mesoporous metal-organic frameworks (MOFs) have been recognized as powerful platforms for drug delivery, especially for biomolecules. Unfortunately, the application of MOFs is restricted due to their relatively poor stability in aqueous media, which is crucial for drug delivery applications. An exception is the porous coordination network (PCN)-series (e.g., PCN-333 and PCN-332), a series of MOFs with outstanding stability in aqueous media at the pH range from 3 to 9. In this study, we fabricate PCN-333 nanoparticles (nPCN) and investigate their stability in different solvents, including water, ethanol, and methanol. Surprisingly, the experimental characterizations in terms of X-ray diffraction, Brunauer-Emmett-Teller (BET), and scanning electron microscopy demonstrated that nPCN is not as stable in water as previously reported. Specifically, the crystalline structure of nPCN lost its typical octahedral shape and even decomposed into an irregular amorphous form when exposed to water for only 2 h, but not when ethanol and methanol were used. Meanwhile, the porosity of nPCN substantially diminished while being exposed to water, as demonstrated by the BET measurement. With the assistance of computational simulations, the mechanism behind the collapse of PCN-333 is illuminated. By molecular dynamics simulation and umbrella sampling, we elucidate that the degradation of PCN-333 occurs by hydrolysis, wherein polar solvent molecules initiate the attack and subsequent breakage of the metal-ligand reversible coordination bonds.