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Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting

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    Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting
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    • Marco E. Zamora
      Marco E. Zamora
      Drexel University, School of Biomedical Engineering, Philadelphia, Pennsylvania 19104, United States
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      More by Marco E. Zamora
      Orcidhttps://orcid.org/0000-0002-7858-307X
    • Serena Omo-Lamai
      Serena Omo-Lamai
      University of Pennsylvania, Department of Bioengineering, Philadelphia, Pennsylvania 19104, United States
      More by Serena Omo-Lamai
    • Manthan N. Patel
      Manthan N. Patel
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      More by Manthan N. Patel
    • Jichuan Wu
      Jichuan Wu
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      More by Jichuan Wu
    • Evguenia Arguiri
      Evguenia Arguiri
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      More by Evguenia Arguiri
    • Vladmir R. Muzykantov
      Vladmir R. Muzykantov
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      More by Vladmir R. Muzykantov
    • Jacob W. Myerson*
      Jacob W. Myerson
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      *E-mail: [email protected]
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    • Oscar A. Marcos-Contreras*
      Oscar A. Marcos-Contreras
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      *E-mail: [email protected]
      More by Oscar A. Marcos-Contreras
    • Jacob S. Brenner*
      Jacob S. Brenner
      University of Pennsylvania, School of Systems Pharmacology and Translational Therapeutics, Philadelphia, Pennsylvania 19104, United States
      University of Pennsylvania, Department of Bioengineering, Philadelphia, Pennsylvania 19104, United States
      *E-mail: [email protected]
      More by Jacob S. Brenner
      Orcidhttps://orcid.org/0000-0001-8437-0161
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    Nano Letters

    Cite this: Nano Lett. 2024, 24, 16, 4774–4784
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    https://doi.org/10.1021/acs.nanolett.3c05031
    Published April 10, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety targeting and physicochemical tropism. Here we directly compare and combine both using intravenous (IV) lipid nanoparticles (LNPs) designed to target the lungs. We utilized PECAM antibodies as affinity moieties and cationic lipids for physicochemical tropism. These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. LNPs combining these targeting methods had >2-fold higher lung uptake than either method alone and markedly enhanced epithelial uptake. To determine if lung uptake is because the lungs are the first organ downstream of IV injection, we compared IV vs intra-arterial (IA) injection into the carotid artery, finding that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the first-pass organ, the brain, among the highest reported. Thus, combining the affinity moiety and physicochemical strategies provides benefits that neither targeting method achieves alone.

    Copyright © 2024 American Chemical Society

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    • Materials and methods; Size and zeta potential for all formulations; Supporting biodistributions; Cell type gating strategy; Cell markers and fluorophores utilized; Supporting uptake and expression (luciferase and eGFP expression); Cell type distributions (PDF)

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    This article is cited by 2 publications.

    1. Yingying Shi, Jiapeng Mao, Sijie Wang, Siyao Ma, Lihua Luo, Jian You. Pharmaceutical strategies for optimized mRNA expression. Biomaterials 2025, 314 , 122853. https://doi.org/10.1016/j.biomaterials.2024.122853
    2. Luigia Serpico, Yuewen Zhu, Renata Faria Maia, Sumedha Sumedha, Mohammad-Ali Shahbazi, Hélder A. Santos. Lipid nanoparticles-based RNA therapies for breast cancer treatment. Drug Delivery and Translational Research 2024, 14 (10) , 2823-2844. https://doi.org/10.1007/s13346-024-01638-2
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    Nano Letters

    Cite this: Nano Lett. 2024, 24, 16, 4774–4784
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.nanolett.3c05031
    Published April 10, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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