Evaluation of the role of surface functionalization of glyco-gold nanoparticles

Nanotechnology has played a critical role in the last years due its fight towards coronavirus disease (COVID-19), with highly effective nanotechnology-based vaccines. However, no successful advances have been observed in the development of nanodrugs to target other global leading causes of death such as autoimmune diseases or cancer. The tropism of nanomaterials towards the liver cells upon intravenous administration is a challenge for its clinical translation, which enhances the need for more selective-targeting strategies. Nonetheless, this can be an opportunity to exploit hepatic diseases such as primary biliary cholangitis (PBC) which have just one therapeutic option, liver transplantation. In this context, the aim of the present PhD was to design a targeting strategy towards macrophages which are involved in adaptive and innate immune responses of several pathophysiological diseases, by using nanoparticles functionalized with glycans for a more selective targeting. The repolarization of macrophages towards a restorative phenotype may lead to an amelioration of the events by approaching novel targeting strategies for clinical translation. For this reason, to deeper understand the life cycle of nanoparticles in the body after intravenous injection in immunocompetent mice, a short and long-term fate study using gold nanoparticles was done. In order to study “if and how” nanoparticles accumulate in the liver cells, different physicochemical parameters were evaluated such as different geometrical shapes, size and polymer coatings. This study was used as a screening to choose the nanoparticles with a higher tropism towards the liver to functionalize the nanoparticles surface with glycans, which have a pivotal role in regulating physiological and pathophysiological conditions, offering a remarkable opportunity to tune immunological responses and inflammation. The design of novel NPs functionalized with a N-glycan that expresses terminal sialic acids may mask NPs from the immune cell response and hepatic degradation. Finally, an innovative approach to design, synthesize and evaluate their biological therapeutic effect on macrophages from PBC by using two different monosaccharides: 1) mannose, which have shown to have anti-inflammatory properties in several autoimmune diseases and be involved in the differentiation of T regulatory cells and; 2) sialic acid, which is also involved in the development of an anti-inflammatory response and suppression of tumour growth. The advancement of nanotechnology-based strategies, provides a new direction in the design of multifunctional nanodevices with a more predictable fate.