Assessing ZIF‐8 Stability for Biomedical Applications Using Fluorescent Probes: Impact of Covalent Conjugation

Metal-organic frameworks (MOFs) have emerged as nanocarriers for biomedical applications. However, their performance under physiological conditions is strongly governed by framework degradation processes occurring at the crystal-solution interface. Here, we systematically investigate the role of surface functionalization in controlling the stability and cargo-release behavior of zeolitic imidazolate framework-8 (ZIF-8) nanoparticles. ZIF-8 surfaces were modified with polyethylene glycol (PEG) derivatives bearing hydroxyl, amino, and imidazole end groups, enabling comparison of different anchoring strategies involving coordinative and covalent interactions. Framework stability, surface modification, and fluorescein release as a model cargo system were evaluated using FTIR spectroscopy, XRPD, STEM, TGA, and UV-vis spectroscopy. Although PEGylation reduced fluorescein release in phosphate-buffered saline compared with unmodified ZIF-8 nanoparticles, the influence of the anchoring group was minimal, demonstrating that PEG coatings provide only limited protection against phosphate-induced surface degradation. To further elucidate the role of interfacial bonding, fluorescein derivatives directly attached to the ZIF-8 framework were investigated as molecular probes of surface stability. While the bonding mode affected dye retention in pure water, this stabilization effect was largely suppressed under phosphate-containing conditions. These results reveal the complex interplay between surface chemistry, framework degradation, and cargo release, providing design considerations for the development of MOF-based biomedical carriers.