Nanogels represent a pivotal class of biomaterials in the therapeutic intracellular treatment of many diseases, especially those involving the central nervous system (CNS). Their biocompatibility and synergy with the biological environment encourage their cellular uptake, releasing the curative cargo in the desired area. As a main drawback, microglia are generally able to phagocytize any foreign element overcoming the blood brain barrier (BBB), including these materials, drastically limiting their bioavailability for the target cells. In this work, we investigated the opportunity to tune and therefore reduce nanogel internalization in microglia cultures, exploiting the orthogonal chemical functionalization with primary amine groups, as a surface coating strategy. Nanogels are designed by following two methods: the direct grafting of aliphatic primary amines and the linkage of -NH2 modified PEG on the nanogel surface. The latter synthesis was proposed to evaluate the combination of PEGylation with the basic nitrogen atom. The achieved results indicate the possibility of effectively modulating the uptake of nanogels, in particular limiting their internalization using the PEG-NH2 coating. This outcome could be considered a promising strategy for the development of carriers for drugs or gene delivery that could overcome microglia scavenging.

Department of Chemistry Materials and Chemical Engineering Giulio Natta Politecnico di Milano via Mancinelli 7 20131 Milan Italy

Department of Engineering and Architecture University of Trieste via Valerio 17 34127 Trieste Italy

Department of Environmental Health Sciences IRCCS Istituto di Ricerche Farmacologiche Mario Negri via La Masa 19 20156 Milan Italy

Department of Informatics Faculty of Science Jan Evangelista Purkyně University Ústí nad Labem Czech Republic

Department of Neuroscience IRCCS Istituto di Ricerche Farmacologiche Mario Negri via La Masa 19 20156 Milan Italy

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