Abstract
Complement is an enzymatic humoral pattern-recognition defence system of the body. Non-specific deposition of blood biomolecules on nanomedicines triggers complement activation through the alternative pathway, but complement-triggering mechanisms of nanomaterials with dimensions comparable to or smaller than many globular blood proteins are unknown. Here we study this using a library of <6 nm poly(amido amine) dendrimers bearing different end-terminal functional groups. Dendrimers are not sensed by C1q and mannan-binding lectin, and hence do not trigger complement activation through these pattern-recognition molecules. While, pyrrolidone- and carboxylic acid-terminated dendrimers fully evade complement response, and independent of factor H modulation, binding of amine-terminated dendrimers to a subset of natural IgM glycoforms triggers complement activation through lectin pathway-IgM axis. These findings contribute to mechanistic understanding of complement surveillance of dendrimeric materials, and provide opportunities for dendrimer-driven engineering of complement-safe nanomedicines and medical devices.
Highlights
G2: 1.056 mM G3: 0.528 mM G4: 0.264 mM G5: 0.132 mM G2 G3(x1017) terminal amine groups mL-1 plasmap = 0.0002 p = 0.0002sC5b-9 in M26 Plasma p = 0.0736 p = 0.003 p = 0.003 p = 0.0001(x1017) terminal amine groups mL-1 plasma0.073 0.146 0.293 0.579 corresponding dendrimer concentrationwithin the G2–G5 family of dendrimers, complement evasion is independent of dendrimer size, geometry and end-terminal functionality
We propose that Angstrom-scale spacing arrangement of dendrimer end-terminal motifs might inherently endow dendrimers to escape sensing by complement pattern-recognition molecules thereby avoiding complement activation through classical and lectin pathways, since the globular target recognition heads in C1q and collectins such as mannan-binding lectin (MBL) bind to target motifs spaced at 2–15 nm apart[17,18,19,20]
We hypothesise that interactions between dendrimers and MBL-binding Ig glycoforms in a functional motif-driven manner might trigger complement activation by enhancing MBL binding to complex oligomannose glycans in IgM
Summary
402 and Asn-563) are occupied by oligomannose glycans that serve as target for MBL21 This glycosylated subset of plasma IgM accounts for ~20% of the total human IgM pool, but pentameric. We hypothesise that interactions between dendrimers and MBL-binding Ig glycoforms in a functional motif-driven manner might trigger complement activation by enhancing MBL binding to complex oligomannose glycans in IgM (and/or IgG). To test this hypothesis first we reverted to the MBL-deficient. C, d Lack of complement activation by Pc-G4 Pyr dendrimer complexes (3.5 mgmL−1) in a typical human plasma determined through measurements of fluid-phase C5a and sC5b-9.
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