Controlling the crystal size and surface chemistry of MOF materials, and understanding their multifunctional effect are of great significance for the biomedical applications of MOF systems. Herein, we designed and synthesized a new anionic MOF, ZJU-64-NSN, which features 1D channels decorated with highly polarized thiadiazole groups, and its crystal size could be systematically tuned from 200 μm to 300 nm through a green and simple approach. As a result, the optimal nanosized ZJU-64-NSN is found to enable an ultrafast loading of cationic drug procainamide (PA) (21.2 wt% within 1 min). Moreover, the undesirable chemical stability of PA@ZJU-64-NSN is greatly improved by the surface coating of polyethylene glycol (PEG) biopolymer. The final drug delivery system PEG/PA@ZJU-64-NSN is found to effectively prevent PA from premature release under the harsh stomach environments due to the intense host-guest interaction, and mainly release PA to the targeted intestinal surroundings. Such controlled drug delivery is proved to be triggered by endogenic Na+ ions instead of H+ ions, well revealed by the study on the dynamics behavior of drug release and UV-Vis absorption spectrum. Good biocompatibility of ZJU-64-NSN and PEG-coated ZJU-64-NSN has been fully demonstrated by MTT assay as well as confocal microscopy imaging.