Balancing Multivalent Avidity and Receptor Availability Governs mRNA Delivery by Antibody-Functionalized Lipid Nanoparticles - PubMed
4 hours ago
- #lipid nanoparticles
- #CAR-T
- #mRNA delivery
- The study focuses on optimizing mRNA delivery using antibody-functionalized lipid nanoparticles (LNPs) for targeted therapy.
- A single-domain antibody (VHH)-LNP platform was developed with controlled orientation and tunable ligand density.
- An antigen-specific ligand binding fluorescence assay was used to quantify functional ligands via single-particle nanoflow cytometry.
- CD8-targeted LNPs showed a bell-shaped dependence of delivery efficiency on ligand density, with an optimal avidity of ~0.1 VHH per 100 nm².
- Excessive ligand density leads to receptor degradation, while optimal avidity balances multivalent engagement with receptor preservation.
- Optimized LNPs achieved selective mRNA expression in CD8+ T cells and enabled in vivo CAR-T generation.
- The study demonstrated dose-dependent B cell depletion at 10-30 μg/kg.
- Surface avidity is identified as a key design parameter for antibody-decorated LNPs, shifting from empirical to rule-based design.