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00925njm 22002777a 4500 dc van Leent, Mandy M T author Meerwaldt, Anu E author Berchouchi, Alexandre author Toner, Yohana C author Burnett, Marianne E author Klein, Emma D author Verschuur, Anna Vera D author Nauta, Sheqouia A author Munitz, Jazz author Prévot, Geoffrey author van Leeuwen, Esther M author Ordikhani, Farideh author Mourits, Vera P author Calcagno, Claudia author Robson, Philip M author Soultanidis, George author Reiner, Thomas author Joosten, Rick R M author Friedrich, Heiner author Madsen, Joren C author Kluza, Ewelina author van der Meel, Roy author Joosten, Leo A B author Netea, Mihai G author Ochando, Jordi author Fayad, Zahi A author Perez-Medina, Carlos author Mulder, Willem J M author Teunissen, Abraham J P author 2021-03 Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1-based nanobiologics with favorable innate immune system-engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation. Sci Adv. 2021; 7(10):eabe7853 10.1126/sciadv.abe7853 2375-2548 Science advances 33674313 http://hdl.handle.net/20.500.12105/13411 A modular approach toward producing nanotherapeutics targeting the innate immune system.