A shift of paradigm: From avoiding nanoparticular complement activation in the field of nanomedicines to its exploitation in the context of vaccine development.

The complement system plays a central role in our innate immunity to fight pathogenic microorganisms, foreign and altered cells, or any modified molecule. Consequences of complement activation include cell lysis, release of histamines, and opsonization of foreign structures in preparation for phagocytosis. Because nanoparticles interact with the immune system in various ways and can massively activate the complement system due to their virus-mimetic size and foreign texture, detrimental side effects have been described after administration like pro-inflammatory responses, inflammation, mild to severe anaphylactic crisis and potentially complement activated-related pseudoallergy (CARPA). Therefore, application of nanotherapeutics has sometimes been observed with restraint, and avoiding or even suppressing complement activation has been of utmost priority. In contrast, in the field of vaccine development, particularly protein-based immunogens that are attached to the surface of nanoparticles, may profit from complement activation regarding breadth and potency of immune response. Improved transport to the regional lymph nodes, enhanced antigen uptake and presentation, as well as beneficial effects on immune cells like B-, T- and follicular dendritic cells may be exploited by strategic nanoparticle design aimed to activate the complement system. However, a shift of paradigm regarding complement activation by nanoparticular vaccines can only be achieved if these beneficial effects are accurately elicited and overshooting effects avoided.