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Post-Conjugation Process for Antibody-Conjugated Lipid Nanoparticles Enabling Tunable Antibody Surface Density for
Feng Qu1,2, Kwadwo Fosu3, Azaria A Wagner1
1Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
ACS Nano
|May 20, 2026
Summary
Antibody-conjugated lipid nanoparticles (Ab-LNPs) can target specific tissues for RNA therapeutics. This study developed a method to control antibody density, optimizing delivery and reducing liver accumulation.
Area of Science:
- Biotechnology
- Nanomedicine
- Drug Delivery
Background:
- Lipid nanoparticles (LNPs) are key nonviral vectors for RNA therapeutics but struggle with extrahepatic targeting due to liver tropism.
- Existing antibody-conjugated LNP (Ab-LNP) methods lack reproducible protocols and reliable quantification of surface antibody density.
Purpose of the Study:
- To develop a reproducible postconjugation formulation protocol for precise control of antibody density on LNPs.
- To establish a quantitative method for determining antibody-to-particle ratio (APR) and assess its impact on Ab-LNP performance.
- To optimize Ab-LNPs for enhanced extrahepatic delivery, specifically targeting bone marrow while minimizing liver uptake.
Main Methods:
- A postconjugation formulation strategy varying Mal-PEG-lipid molar percentages (0.05%, 0.2%, 0.5%) to tune antibody density.
- Label-free quantification of antibody-to-particle ratio (APR) using orthogonal distance regression and Monte Carlo uncertainty propagation.
- Flow-through purification, colloidal stability assessment, biophysical characterization, noncellular binding, cellular uptake, and in vivo biodistribution studies in a mouse xenograft model.
Main Results:
- Precise tuning of antibody densities achieved reproducible APRs of ~340, ~760, and ~1200.
- Formulations demonstrated excellent colloidal stability (>1 month at 4 °C).
- Low-density Ab-LNPs (lower APR) exhibited superior binding and cellular uptake, with enhanced bone marrow accumulation in vivo, while minimizing off-target liver sequestration.
Conclusions:
- Antibody-to-particle ratio (APR) is a critical quality attribute for Ab-LNP design.
- An optimal antibody density window exists that balances targeted delivery with reduced hepatic entrapment.
- The developed tunable Ab-LNP platform offers a rational approach for designing targeted RNA delivery systems.
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