Enhanced immunocompatibility and hemocompatibility of nanomedicines across multiple species using complement pathway inhibitors

Li, Yue, Jacques, Sarah, Gaikwad, Hanmant, Nebbia, Morgan, Banda, Nirmal K., Holers, V. Michael, Tomlinson, Stephen A., Scheinman, Robert I., Monte, Andrew, Saba, Laura, Lasda, Erika, Hasselberth, Jay, Busquet, Nicolas, Zelek, Wioleta M., Moghimi, S. Moein and Simberg, Dmitri 2025. Enhanced immunocompatibility and hemocompatibility of nanomedicines across multiple species using complement pathway inhibitors. Science Advances 11 (28) , eadw1731. 10.1126/sciadv.adw1731

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	2375-2548
Date of First Compliant Deposit:	15 July 2025
Date of Acceptance:	14 May 2025
Last Modified:	15 Jul 2025 14:30
URI:	https://orca.cardiff.ac.uk/id/eprint/179801

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