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Lookup NU author(s): Professor Moein MoghimiORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
The activation of complement by nanomedicines triggers immune uptake and proinflammatory responses. Complement pathway inhibitors could offer strategies to address these challenges. Here, we assess the efficacy of inhibitors with various nanoparticles, including dextran superparamagnetic iron oxide nanoworms, polyethylene glycol (PEG) liposomal drugs, and mRNA lipid nanoparticles. In human sera, inhibitors of the alternative pathway iptacopan and danicopan exhibit variable efficacies, ranging from high nanomolar to incomplete inhibition. However, both iptacopan and danicopan display poor efficacy with PEGylated liposomal doxorubicin. Sutimlimab, an inhibitor of the classical pathway, demonstrates poor efficacy with PEGylated liposomal doxorubicin, even in sera with anti-PEG antibodies. Iptacopan displays donor-dependent inhibition of the uptake of nanoparticles in human blood. Bolus coadministration of iptacopan with nanoworms in mice, rats, and dogs inhibits C3 opsonization and uptake by granulocytes. Iptacopan also alleviates nanoparticle-induced lethargy in rats and severe hypotension in dogs. These data suggest that complement inhibitors can enhance the immunocompatibility and hemocompatibility of nanomedicines in a donor-dependent manner.
Author(s): Li Y, Jacques S, Gaikwad H, Nebbia M, Banda NK, Holers VM, Tomlinson SA, Scheinman RI, Monte A, Saba L, Lasda E, Hasselberth J, Busquet N, Zelek WM, Moghimi SM, Simberg D
Publication type: Article
Publication status: Published
Journal: Science Advances
Year: 2025
Volume: 11
Issue: 28
Online publication date: 09/07/2025
Acceptance date: 14/05/2025
Date deposited: 28/07/2025
ISSN (electronic): 2375-2548
Publisher: American Association for the Advancement of Science
URL: https://doi.org/10.1126/sciadv.adw1731
DOI: 10.1126/sciadv.adw1731
Data Access Statement: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
PubMed id: 40632862
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