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Abstract
Vascular endothelial cells (ECs) play a central role in the pathophysiology of many diseases. The use of targeted nanoparticles (NPs) to deliver therapeutics to ECs could dramatically improve efficacy by providing elevated and sustained intracellular drug levels. However, achieving sufficient levels of NP targeting in human settings remains elusive. Here, we overcome this barrier by engineering a monobody adapter that presents antibodies on the NP surface in a manner that fully preserves their antigen-binding function. This system improves targeting efficacy in cultured ECs under flow by >1000-fold over conventional antibody immobilization using amine coupling and enables robust delivery of NPs to the ECs of human kidneys undergoing ex vivo perfusion, a clinical setting used for organ transplant. Our monobody adapter also enables a simple plug-and-play capacity that facilitates the evaluation of a diverse array of targeted NPs. This technology has the potential to simplify and possibly accelerate both the development and clinical translation of EC-targeted nanomedicines.
Targeted nanoparticle delivery to sites of interest is important for targeted therapeutics. Here, the authors improve the targeting efficiency of antibodies on nanoparticles using a monobody adapter to correctly orientate the antibody to preserve targeting function and demonstrate application in targeting the vascular endothelium of human kidneys.
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1 Yale University, Department of Biomedical Engineering, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)
2 New York University Langone Medical Center, Perlmutter Cancer Center, New York, USA (GRID:grid.240324.3) (ISNI:0000 0001 2109 4251); New York University School of Medicine, Department of Medicine, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753)
3 Yale University, Department of Surgery, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)
4 Yale University, Department of Biomedical Engineering, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale University, Department of Surgery, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)
5 Yale University, Department of Molecular Biophysics and Biochemistry, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)
6 New York University Langone Medical Center, Perlmutter Cancer Center, New York, USA (GRID:grid.240324.3) (ISNI:0000 0001 2109 4251)
7 New York University Langone Medical Center, Perlmutter Cancer Center, New York, USA (GRID:grid.240324.3) (ISNI:0000 0001 2109 4251); New York University School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753)
8 Yale University, Department of Pathology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)
9 University of Cambridge, Department of Surgery, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934)
10 Yale University, Department of Immunobiology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)