Metal nanoparticles are established tools for biomedical applications due to their unique optical properties, primarily attributed to localized surface plasmon resonances. They show distinct optical characteristics, such as high extinction cross-sections and resonances at specific wavelengths, which are tunable across the wavelength spectrum by modifying the nanoparticle geometry. These attributes make metal nanoparticles highly valuable for sensing and imaging in biology and medicine. However, their widespread adoption is hindered due to challenges in consistent and accurate nanoparticle fabrication and functionality as well as due to nanotoxicological concerns, including cell damage, DNA damage, and unregulated cell signaling. In this study, we present a fabrication approach using nanoimprint lithography in combination with thin film deposition which yields highly homogenous nanoparticles in size, shape and optical properties with standard deviations of the main geometry parameters of less than 5% batch-to-batch variation. The measured optical properties closely match performed simulations, indicating that pre-experimental modelling can effectively guide the design of nanoparticles with tailored optical properties. Our approach also enables nanoparticle transfer to solution. Particularly, we show that the surface coating with a PEG polymer shell ensures stable dispersions in buffer solutions and complex cell media for at least 7 days. Furthermore, our in vitro experiments demonstrate that these nanoparticles are internalized by cells via endocytosis, exhibit good biocompatibility, and show minor cytotoxicity, as evidenced by high cell viability. In the future, our high-precision nanoparticle fabrication method together with tunable surface plasmon resonance and reduced nanotoxicity will offer the possibility to replace conventional nanomaterials for biomedical applications that make use of an optical response at precise wavelengths. This includes the use of the nanoparticles as contrast agents for imaging, as probes for targeted photothermal cancer therapy, as carriers for controlled drug delivery, or as probes for sensing applications based on optical detection principles.

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 in vitro, 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.