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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.<\/jats:p>","DOI":"10.1126\/sciadv.adw1731","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T17:58:57Z","timestamp":1752083937000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["Enhanced immunocompatibility and hemocompatibility of nanomedicines across multiple species using complement pathway inhibitors"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-8074","authenticated-orcid":true,"given":"Yue","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2269-4831","authenticated-orcid":true,"given":"Sarah","family":"Jacques","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-0545","authenticated-orcid":true,"given":"Hanmant","family":"Gaikwad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5078-3530","authenticated-orcid":true,"given":"Morgan","family":"Nebbia","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5291-5136","authenticated-orcid":true,"given":"Nirmal K.","family":"Banda","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5634-7746","authenticated-orcid":true,"given":"V. 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