Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement

PEGylation of lipid-based nanoparticles and other nanocarriers is widely used to increase their stability and plasma half-life. However, either pre-existing or de novo formed anti-PEG antibodies can induce hypersensitivity reactions and accelerated blood clearance through binding to the nanoparticle...

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Bibliographic Details
Published in:Journal of controlled release 2022-01, Vol.341, p.475-486
Main Authors: Estapé Senti, Mariona, de Jongh, Caroline A., Dijkxhoorn, Kim, Verhoef, Johan J.F., Szebeni, Janos, Storm, Gert, Hack, C. Erik, Schiffelers, Raymond M., Fens, Marcel H., Boross, Peter
Format: Article
Language:English
Subjects:
Anti-PEG antibodies
Complement
Liposomes
LNPs
PEG
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Summary:PEGylation of lipid-based nanoparticles and other nanocarriers is widely used to increase their stability and plasma half-life. However, either pre-existing or de novo formed anti-PEG antibodies can induce hypersensitivity reactions and accelerated blood clearance through binding to the nanoparticle surfaces, leading to activation of the complement system. In this study, we investigated the consequences and mechanisms of complement activation by anti-PEG antibodies interacting with different types of PEGylated lipid-based nanoparticles. By using both liposomes loaded with different (model) drugs and LNPs loaded with mRNA, we demonstrate that complement activation triggered by anti-PEG antibodies can compromise the bilayer/surface integrity, leading to premature drug release or exposure of their mRNA contents to serum proteins. Anti-PEG antibodies also can induce deposition of complement fragments onto the surface of PEGylated lipid-based nanoparticles and induce the release of fluid phase complement activation products. The role of the different complement pathways activated by lipid-based nanoparticles was studied using deficient sera and/or inhibitory antibodies. We identified a major role for the classical complement pathway in the early activation events leading to the activation of C3. Our data also confirm the essential role of amplification of C3 activation by alternative pathway components in the lysis of liposomes. Finally, the levels of pre-existing anti-PEG IgM antibodies in plasma of healthy donors correlated with the degree of complement activation (fixation and lysis) induced upon exposure to PEGylated liposomes and mRNA-LNPs. Taken together, anti-PEG antibodies trigger complement activation by PEGylated lipid-based nanoparticles, which can potentially compromise their integrity, leading to premature drug release or cargo exposure to serum proteins. [Display omitted] •Pre-existing anti-PEG Abs in human serum induce activation of complement.•Classical pathway drives initial activation, amplification is crucial for lytic pathway.•Complement fragments deposit on the surface of immobilized PEGylated liposomes.•Complement activation triggered by anti-PEG Abs compromises lipid-based NP integrity.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2021.11.042