The Nano-War Against Complement Proteins

Abstract

Targeted drug delivery and nanomedicine hold the potential promise of delivering drugs solely to target organs or cell types, thus decreasing off-target side effects and improving efficacy. However, nano-scale drug carriers face several barriers to this goal, with one of the most formidable being the complement cascade. Complement proteins, especially C3, opsonize not just the microbes they evolved to contain, but also nanocarriers. This results in multiple problems, including marking the nanocarriers for clearance by leukocytes, likely fouling of the targeting moieties on nanocarriers, and release of toxins which produce deleterious local and systemic effects. Here, we review how complement achieves its blockade of nanomedicine, which nanocarrier materials properties best avoid complement, and current and future strategies to control complement to unleash nanomedicine's potential.

A Robust and Efficient Method to Purify DNA-Scaffolded Nanostructures by Gravity-Driven Size Exclusion Chromatography

“…More AFM images of protein and IgGmodified origami were included in Figure S10. Next, we used IgG origami to study the spatial effect of the activation of complement protein reactions, 31 which was a part of the innate immune system. C3 is the most abundant complement protein, and the activation of C3 results in the cleavage of C3 to produce C3a, which is a soluble fragment, and C3b, which forms adducts onto the surface nucleophiles (e.g., antibodies immobilized on DNA origami).…”

Package delivered: folate receptor-mediated transporters in cancer therapy and diagnosis

“…For example, complement receptors on leukocytes can bind NCs decorated by complement factors; thereby, NCs are taken up by these cells via phagocytosis. 283 Scavenger receptors bind to lipoproteins and regulate the activity of dendritic cells and macrophages by interacting with toll-like receptors. Finally, Fc receptors can interact with antibodies coated on the NC surface to allow NC targeting.…”

Marginated neutrophils in the lungs effectively compete for nanoparticles targeted to the endothelium, serving as a part of the reticuloendothelial system

“…Previously we have shown that complement proteins can substantially impact the biodistribution of targeted nanoparticles. 41,[75][76][77] We began with in vitro studies to determine if complement proteins were indeed opsonizing our nanoparticles. We used a nanoparticle tracking analysis (NTA) assay (Supp Videos 6-8) that we previously validated for measuring the opsonization of nanoparticles by the main complement opsonin, C3 41,77 .…”