Schrijver, David PRöring, Rutger JDeckers, Jeroende Dreu, AnneToner, Yohana CPrevot, GeoffreyPriem, BramMunitz, JazzNugraha, Eveline Gvan Elsas, YuriAzzun, AnthonyAnbergen, TomGroh, Laszlo ABecker, Anouk M DPérez-Medina, CarlosOosterwijk, Roderick SNovakovic, BorisMoorlag, Simone J C F MJansen, AronPickkers, PeterKox, MatthijsBeldman, Thijs JKluza, Ewelinavan Leent, Mandy M TTeunissen, Abraham J Pvan der Meel, RoyFayad, Zahi AJoosten, Leo A BFisher, Edward AMerkx, MaartenNetea, Mihai GMulder, Willem J M2023-09-052023-09-052023-06-08Nat Biomed Eng. 2023 Jun 8.http://hdl.handle.net/20.500.12105/16412Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.engVoRhttp://creativecommons.org/licenses/by/4.0/Atribución 4.0 Internacional3729143310.1038/s41551-023-01050-02157-846XNature biomedical engineeringopen access