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

Nat Nanotechnol. 2024 Feb;19(2):246-254. doi: 10.1038/s41565-023-01514-z. Epub 2023 Oct 5.


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.

MeSH terms

  • Animals
  • Complement Activation
  • Complement C3
  • Humans
  • Mice
  • Nanoparticles*
  • Rats
  • Receptors, Complement 3b
  • Receptors, Complement 3d*
  • Recombinant Fusion Proteins


  • Receptors, Complement 3d
  • Receptors, Complement 3b
  • Complement C3
  • CR2-Crry fusion protein, mouse
  • Recombinant Fusion Proteins