Clickable Polymer-Based Coatings for Modulating the Interaction of Metal–Organic Framework Nanocrystals with Living Cells

Nanosized microporous metal-organic-frameworks (NMOFs) serve as versatile drug delivery systems capable of navigating complex microenvironments and interacting with cells in specific tissues. The physicochemical properties of NMOFs, such as size, composition, porosity, colloidal stability, and external surface functionalization are essential for their success as efficient carriers. This study introduces a flexible, clickable coating using an amphiphilic polymer derivatized with dibenzo cyclooctyne groups as a universal, postsynthetic functionalization tool. To prove its universality, nanosized MOFs with different structure and composition (UiO-67, NU-1000, PCN-222, and ZIF-8) were produced with high monodispersity and were coated with a clickable, amphiphilic polymer. The resulting polymer-coated NMOFs display exceptional colloidal and structural stability in different biologically relevant media. For comparative purposes, we selected two size-equivalent NMOFs, ZIF-8 and UiO-67, which were functionalized with a library of biologically relevant azide-derivatized (macro)molecules, including poly(ethylene glycol), mannose, and a dynein-binding cell-penetrating peptide, using a bioorthogonal reaction. The choice of ZIF-8 and UiO-67, both 150 nm in size but with distinct coordination and surface chemistries, is pivotal due to their differing acid and base stability characteristics, which may potentially influence their performance in cellular environments. To track their performance <i>in vitro</i>, the NMOFs were loaded with cresyl violet, a common histological stain and lysosomal marker. Cellular internalization of the surface-functionalized NMOFs was markedly governed by their distinct (macro)molecule characteristics. This demonstrates that surface properties critically influence uptake efficiency, while also highlighting the versatility and effectiveness of the proposed coating strategy. In particular, the one functionalized with the dynein-binding peptide demonstrated a markedly higher rate of cellular internalization compared to other NMOFs. In contrast, derivatizations with mannose and poly(ethylene glycol) are associated with a substantial reduction in cellular uptake, suggesting stealth behavior. These results provide a bioorthogonal and versatile alternative for the external surface engineering of NMOFs, aiming to improve targeted drug delivery effectiveness.