Multifunctional theranostic nanocarrier platform for microglia-selective cytochalasin D delivery to modulate neuroinflammation after acute brain injuries

Biomaterials, vol. 337, pp. 124495

Abstract

Targeting microglia to modulate neuroinflammation after acute brain injuries (ABIs) is promising but limited by poor blood-brain barrier (BBB) penetration and systemic toxicity of candidate agents. In addition, multifunctional platforms combining targeted therapy with real-time traceability remain limited. We developed and characterized a multifunctional theranostic, folate-functionalized, polydopamine (PDA)-coated mesoporous silica nanoparticle (FA-NP) system for microglia-selective delivery and intracellular release of cytoskeleton inhibitor Cytochalasin D (CytoD). FA-NPs exhibited ideal physicochemical properties for parenchymal brain accumulation and pH-sensitive PDA shells enabled intracellular retention and gradual degradation. Using radiolabeled and fluorescein-isothiocyanate-functionalized FA-NPs, SPECT/CT imaging, γ-counting, autoradiography, and immunohistochemistry confirmed parenchymal brain accumulation with cellular uptake following systemic administration. Activated microglia upregulated folate receptors (FOLR1/2) and internalized FA-NPs via FOLR-mediated, dynamin-dependent endocytosis. CytoD-loaded FA-NPs (FA-NP[CytoD]) significantly reduced microglial migration, phagocytosis, ROS production, and proinflammatory cytokines, outperforming molecular CytoD while exhibiting notably lower toxicity compared to both CytoD and unfunctionalized particles. In organotypic brain slice models of hypoxia-reoxygenation and traumatic injury, FA-NP[CytoD] reduced inflammation at 24 and 96 h. Systemic administration enabled brain accumulation with clearance over time. Together, this multifunctional theranostic platform integrates selective microglial targeting, controlled drug release, and multimodal imaging, offering translational potential for ABIs.

Authors 15

1. Sabri E. M. Sahnoun Aachen Department of Nuclear Medicine

   University of Oxford · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany; Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom

2. Rozina Noristani

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, 94305, USA

3. Paolo Alimonti

   Brigham and Women's Hospital · Harvard University · University of Oxford

   Affiliation as printed

   Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02120, USA

4. Jonas Pes Aachen Department of Neurology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany

5. Lara Gubeljak Aachen Department of Neurology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany

6. Annika Szymura

   University of Cologne

   Affiliation as printed

   Institute of Inorganic and Materials Chemistry, University of Cologne, Cologne, 50939, Germany

7. Shaista Ilyas

   University of Cologne

   Affiliation as printed

   Institute of Inorganic and Materials Chemistry, University of Cologne, Cologne, 50939, Germany

8. Eren Arik Aachen Department of Neurology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany

9. Alexandru Florea Aachen Department of Nuclear Medicine

   Maastricht University Medical Centre · Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, 6202, The Netherlands

10. Eva Miriam Buhl Aachen Electron Microscopy Facility Institute of Pathology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Electron Microscopy Facility, Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany

11. Bernd Neumaier

    Forschungszentrum Jülich · University of Cologne · University Hospital Cologne

    Affiliation as printed

    Institute of Radiochemistry and Experimental Molecular Imaging, University Hospital Cologne, University of Cologne, Cologne, 50937, Germany; Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, Jülich, 52425, Germany

12. Sanjay Mathur

    University of Cologne

    Affiliation as printed

    Institute of Inorganic and Materials Chemistry, University of Cologne, Cologne, 50939, Germany

13. Jörg B. Schulz Aachen Department of Neurology JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging

    Forschungszentrum Jülich · Universitätsklinikum Aachen · Jülich Aachen Research Alliance · RWTH Aachen University

    Affiliation as printed

    Department of Neurology, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany; JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, 52074, Germany

14. Felix Manuel Mottaghy Aachen Department of Nuclear Medicine

    Maastricht University Medical Centre · Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, 6202, The Netherlands

15. Pardes Habib Aachen Department of Neurology

    Universitätsklinikum Aachen · Stanford Medicine · RWTH Aachen University · Stanford University

    Affiliation as printed

    Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, 94305, USA; Department of Neurology, University Hospital Aachen, RWTH Aachen University, Aachen, 52074, Germany. Electronic address: phabib@stanford.edu