2. Academic Validation
  3. A modular approach toward producing nanotherapeutics targeting the innate immune system

A modular approach toward producing nanotherapeutics targeting the innate immune system

  • Sci Adv. 2021 Mar 5;7(10):eabe7853. doi: 10.1126/sciadv.abe7853.
Mandy M T van Leent 1 2,  Anu E Meerwaldt 1 3,  Alexandre Berchouchi 1,  Yohana C Toner 1,  Marianne E Burnett 1,  Emma D Klein 1,  Anna Vera D Verschuur 1,  Sheqouia A Nauta 1,  Jazz Munitz 1,  Geoffrey Prévot 1,  Esther M van Leeuwen 1,  Farideh Ordikhani 4,  Vera P Mourits 5,  Claudia Calcagno 1,  Philip M Robson 1,  George Soultanidis 1,  Thomas Reiner 6 7 8,  Rick R M Joosten 9,  Heiner Friedrich 9 10,  Joren C Madsen 11,  Ewelina Kluza 10 12,  Roy van der Meel 10 12,  Leo A B Joosten 5,  Mihai G Netea 5 13,  Jordi Ochando 4,  Zahi A Fayad 1,  Carlos Pérez-Medina 14,  Willem J M Mulder 15 10 12,  Abraham J P Teunissen 15
Affiliations

Affiliations

  • 1 Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, Netherlands.
  • 3 Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht/Utrecht University, Utrecht, Netherlands.
  • 4 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands.
  • 6 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 Department of Radiology, Weill Cornell Medical College, New York, NY, USA.
  • 8 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9 Center of Multiscale Electron Microscopy, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, Netherlands.
  • 10 Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, Netherlands.
  • 11 Center for Transplantation Sciences and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • 12 Laboratory of Chemical Biology, Department of Biochemical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.
  • 13 Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
  • 14 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 15 Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. bram.teunissen@mssm.edu willem.mulder@mssm.edu.
PMID: 33674313 DOI: 10.1126/sciadv.abe7853
Abstract

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.

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