Exogenous CD55 Expression on Membrane-Wrapped Nanoparticles Unexpectedly Increases Spleen Tropism and Immune Cell Uptake

Intravenously delivered nanoparticle (NP) therapies have the potential to cure a variety of diseases; however, their clinical use has been stunted by undesirable levels of immune cell clearance. This clearance is attributed to protein adsorption onto the outside of the NPs, leading to recognition by immune cells and subsequent accumulation in the liver and spleen. Membrane-wrapped nanoparticles (MWNPs) offer a potential solution to reducing immune clearance by incorporating immune evasion/marker-of-self-proteins, although they too exhibit protein corona-mediated clearance. While various opsonin proteins can bind to MWNPs, complement proteins are particularly problematic as they play a crucial role in innate immunity, triggering immune cell recognition and clearance and causing inflammation. We hypothesized that introducing a complement regulatory protein into the membranes of MWNPs could minimize complement-mediated clearance, but the opposite effect was observed experimentally. In this study, before membrane collection, source cells were genetically modified to express the complement regulatory protein, CD55, which inhibits C3 convertases, key enzymes in the complement cascade. We confirmed that the active protein was transferred onto MWNPs and determined that CD55-modified MWNPs incubated in mouse serum significantly reduced C3 convertase concentration by 33% compared to unmodified MWNPs. Unexpectedly,