Inhibition of acute complement responses towards bolus-injected nanoparticles using targeted short-circulating regulatory proteins.

Autor: Li Y; Translational Bio-Nanosciences Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Jacques S; Translational Bio-Nanosciences Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Gaikwad H; Translational Bio-Nanosciences Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Wang G; Translational Bio-Nanosciences Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Banda NK; Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Holers VM; Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Scheinman RI; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Tomlinson S; Medical University of South Carolina Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.; Ralph Johnson Veterans Affairs Medical Center, Charleston, SC, USA., Moghimi SM; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; School of Pharmacy, Newcastle University, Newcastle upon Tyne, UK.; Translational and Clinical Research Institute, Faculty of Health and Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Simberg D; Translational Bio-Nanosciences Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. dmitri.simberg@cuanschutz.edu.; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. dmitri.simberg@cuanschutz.edu.; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. dmitri.simberg@cuanschutz.edu.
Jazyk: angličtina
Zdroj: Nature nanotechnology [Nat Nanotechnol] 2024 Feb; Vol. 19 (2), pp. 246-254. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1038/s41565-023-01514-z
Abstrakt: Effective inhibition of the complement system is needed to prevent the accelerated clearance of nanomaterials by complement cascade and inflammatory responses. Here we show that a fusion construct consisting of human complement receptor 2 (CR2) (which recognizes nanosurface-deposited complement 3 (C3)) and complement receptor 1 (CR1) (which blocks C3 convertases) inhibits complement activation with picomolar to low nanomolar efficacy on many types of nanomaterial. We demonstrate that only a small percentage of nanoparticles are randomly opsonized with C3 both in vitro and in vivo, and CR2-CR1 immediately homes in on this subpopulation. Despite rapid in vivo clearance, the co-injection of CR2-CR1 in rats, or its mouse orthologue CR2-Crry in mice, with superparamagnetic iron oxide nanoparticles nearly completely blocks complement opsonization and unwanted granulocyte/monocyte uptake. Furthermore, the inhibitor completely prevents lethargy caused by bolus-injected nanoparticles, without inducing long-lasting complement suppression. These findings suggest the potential of the targeted complement regulators for clinical evaluation.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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