Nuzhat Maisha - PhD Proposal Defense

Nuzhat Maisha

The complement pathway is a part of the innate immune system responsible for getting rid of threats to the immune system. However, complement activation can lead to the unwanted clearance of therapeutic nanomaterials as the immune system considers the nanoparticles as a foreign agent, resulting in complement-mediated hypersensitivity reactions and cause anaphylaxis, which can even be fatal. Moreover, terminal complexes formed along the pathway can also cause lysis and degradation of the nanoparticles, altering the biodistribution of the therapeutic. As 7-10% of the human population are prone to complement activation, this is a significant safety concern while developing nanoformulations. Since materials properties and surface architecture of nanoparticles are significant contributors to the complement response, we hypothesize that tuning materials properties would generate stealth nanoparticles that do not activate the complement pathways. Hence our research questions are: 1) What is the impact of surface architecture and materials properties of nanoparticles on complement activation? 2) What are the suitable sample preparation techniques and assay conditions for investigating complement-mediated hypersensitivity reactions in vitro? 3) Does the in vitro complement-mediated response mimic the in vivo response? 4) What is the impact of materials properties on the pathway of activation?

To answer these questions, we are developing complement assays that are highly sensitive and can assess the complement-mediated response in vitro, mimicking the in vivo response with precision. The developed assay will be deployed to investigate the role of surface moieties and coatings in generating the complement-mediated response in vitro and in vivo. Lastly, we will use the developed technique for tracking complement response with sensitivity and precision in understanding how different materials properties impact the complement-mediated response and develop a library of nanomaterials properties-complement interaction patterns. Overall, the knowledge gathered in this study will be used to design stealth nanomaterials for therapeutic applications to overcome initial infusion reactions