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Oxidized mRNA Lipid Nanoparticles for In Situ Chimeric Antigen Receptor Monocyte Engineering
Alvin J Mukalel1, Alex G Hamilton1, Margaret M Billingsley1
1Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Advanced Functional Materials
|December 4, 2024
Summary
Researchers developed oxidized lipid nanoparticles (oLNPs) for in situ engineering of chimeric antigen receptor (CAR) monocytes. This novel approach enhances CAR monocyte therapy for solid tumors, improving delivery and reducing toxicity.
Area of Science:
- Immunotherapy
- Nanomedicine
- Cell Engineering
Background:
- Chimeric antigen receptor (CAR) monocyte and macrophage therapies show promise for solid tumors but face challenges with conventional CAR T cell therapy.
- Messenger RNA lipid nanoparticles (mRNA-LNPs) enable in situ engineering of CAR monocytes, offering transient expression to minimize off-tumor toxicity and simplify manufacturing.
- Identifying LNPs with specific monocyte tropism and effective intracellular delivery remains a hurdle for traditional screening methods.
Purpose of the Study:
- To develop a novel class of oxidized lipid nanoparticles (oLNPs) with inherent tropism and mRNA delivery capabilities for monocytes.
- To overcome limitations in identifying suitable LNPs for monocyte-based immunotherapies through advanced screening techniques.
Main Methods:
- Synthesis and evaluation of a library of oxidized (oLNPs) and unoxidized LNPs (uLNPs) for mRNA delivery to immune cells.
- Characterization of oLNPs for differences in morphology, ionization energy, and pKa, assessing their impact on delivery to macrophages versus T cells.
- High-throughput in vivo screening using DNA barcodes to identify oLNP formulations with monocyte tropism.
Main Results:
- oLNPs exhibited distinct properties, enhancing mRNA delivery to human macrophages but not T cells.
- An oLNP formulation, C14-O2, was identified with innate tropism to monocytes via in vivo screening.
- In a proof-of-concept, C14-O2 engineered functional CD19-CAR monocytes in situ, inducing significant B cell aplasia in mice.
Conclusions:
- Oxidized LNPs represent a promising platform for in situ engineering of CAR monocytes and macrophages.
- This technology has the potential to advance CAR monocyte therapy for solid tumors by improving targeting and efficacy.
- The developed oLNP system offers a viable strategy to overcome challenges associated with current CAR T cell therapies.
