The mechanisms of anti-PEG immune response are different in the spleen and the lymph nodes.

Polyethylene glycol (PEG) is a common ingredient in nanomedicines and pharmaceuticals. Recent studies show that approximately 20-70% of humans have anti-PEG antibodies that can recognize the polymer. Because these anti-PEG antibodies can reduce the effectiveness of certain PEGylated therapeutics, understanding how these immunoglobulins are produced is important. In this work, we investigate the mechanisms of the anti-PEG immune response, following the injection of polymeric nanoparticles by different routes of administration. We observed that the extent of systemic absorption and splenic deposition cannot predict the production of anti-PEG IgM - possibly because redundant biological pathways can be involved. Data obtained by surgically removing the spleen or depleting the complement activity suggest that the mechanisms behind the anti-PEG immune response differ between intravenous and subcutaneous injections. While B cells from the spleen appear to necessitate complement proteins to interact with nanoparticles, internalization by follicular B cells from the lymph nodes is unaffected by depletion of the cascade. This study confirms that the biological mechanisms involved in the immune recognition of nanomedicines varies based on the administration route. This knowledge can be utilized to use nanomedicines to engage the immune system in differentiated ways.