Decoy nanoparticles bearing native C5a receptors as a new approach to inhibit complement-mediated neutrophil...

Complement-activated neutrophils are integrally involved in many pathological conditions as well as in dampening the efficacy of cell-based therapies. Mesenchymal stem cells (MSCs) hold promise for regenerative medicine and inflammatory disease therapy, but current MSC-based therapies still require further improvements to ensure success. We recently reported that immediately upon delivery to the bloodstream, MSCs activate complement to produce C5a, which binds to its receptor, C5aR, on neutrophils and thus activates these cells to damage MSCs. Thus, blocking this C5a-C5aR interaction should yield improvements in MSC survival and treatment efficacy. In this project, we developed decoy nanoparticles with surface displaying native C5aR by coating membrane vesicles derived from macrophages expressing high levels of C5aR onto poly(lactic-co-glycolic acid) (PLGA) cores. These C5aR-displaying decoy nanoparticles effectively inhibited neutrophil activation and thus reduced sequential injury to MSCs upon exposure to blood both in vitro and in vivo. Consequently, survival and treatment potency of the MSCs were significantly improved by these decoy nanoparticles. This finding suggests that the C5aR-displaying decoy nanoparticles represent a unique approach toward improving current MSC-based therapies. Additionally, these decoy nanoparticles can be useful as a new reagent for the treatment of other pathological conditions that involve C5a-C5aR signaling. STATEMENT OF SIGNIFICANCE: Complement C5aR has been implied in the pathogenesis of many disorders and is emerging as a new target for the development of therapeutics. So far all the inhibitors of C5aR are either biologicals or small compounds with various shortcomings. Since C5aR is a G-protein coupled receptor that features a multi-loop binding interface with its ligand, C5a, soluble forms of C5aR as decoys for cell surface C5aR are unlikely. We believe this is the first evidence suggesting that C5aR decoy nanoparticles can be developed to treat various C5aR-mediated pathological conditions.