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Balancing Multivalent Avidity and Receptor Availability Governs mRNA Delivery by Antibody-Functionalized Lipid

Kazuki Hashiba1, Masahiro Fukasaka1, Chisa Okuma1

  • 1Nucleic Acid Medicine Business Division, Nitto Denko Corporation, 1-1-2 Shimohozumi, Ibaraki, Osaka 567-8680, Japan.

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Summary

Researchers developed antibody-functionalized lipid nanoparticles (LNPs) for targeted mRNA delivery. Optimal surface avidity was identified, enabling selective delivery to CD8+ T cells and in vivo CAR-T generation for cancer therapy.

Keywords:
CAR-Tantibodyionizable lipidslipid nanoparticlesmRNA delivery

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Area of Science:

  • Biotechnology
  • Immunology
  • Nanomedicine

Background:

  • Messenger RNA (mRNA) therapeutics require targeted delivery systems for enhanced efficacy and safety.
  • Antibody-functionalized lipid nanoparticles (LNPs) offer programmable targeting, but quantitative relationships between surface properties and delivery efficiency are not well understood.

Purpose of the Study:

  • To establish a quantitative framework for designing antibody-decorated LNPs with controlled targeting.
  • To determine the optimal surface avidity for efficient and selective mRNA delivery to target cells.

Main Methods:

  • Developed a VHH-LNP platform with controlled orientation and tunable ligand density.
  • Utilized a single-particle nanoflow cytometry assay to quantify functional ligands and measure binding avidity.
  • Assessed mRNA delivery efficiency and cellular responses in vitro and in vivo.

Main Results:

  • Demonstrated a bell-shaped dependence of LNP delivery efficiency on ligand density, with an optimal avidity of ~0.1 VHH per 100 nm².
  • Showed that excessive ligand density leads to receptor degradation, while optimal avidity balances engagement and receptor preservation.
  • Achieved selective mRNA expression in CD8+ T cells and successful in vivo CAR-T generation, leading to B cell depletion.

Conclusions:

  • Surface avidity is a critical quantitative parameter for designing antibody-functionalized LNPs.
  • This work transforms LNP engineering from an empirical process to a rule-based design approach for targeted mRNA therapeutics.
  • Optimized LNPs hold promise for in vivo generation of CAR-T cells and other immunotherapies.