β-Hydroxy Thioether-Derived Ionizable Lipids for Spleen-Tropic mRNA Delivery and In Vivo Chimeric Antigen Receptor T...

Area of Science:

• Biotechnology
• Immunotherapy
• Drug Delivery

Background:

• In vivo generation of chimeric antigen receptor (CAR) T cells using nucleic acid delivery via lipid nanoparticles (LNPs) is a promising therapeutic strategy.
• Low efficiency of in vivo gene delivery to T cells remains a significant hurdle for this approach.

Purpose of the Study:

• To develop and evaluate novel ionizable lipids for efficient in vivo mRNA delivery to T cells.
• To identify superior LNP formulations for enhancing CAR T cell therapy.

Main Methods:

• A combinatorial library of ionizable lipids based on a β-hydroxy thioether scaffold was synthesized.
• 300 distinct ionizable lipids were evaluated for mRNA delivery efficacy in vitro and in vivo using a luciferase reporter assay.
• The leading LNP candidate, 113-AA-C8C14, was tested for its ability to generate CAR T cells and its therapeutic efficacy in a pancreatic cancer mouse model.

Main Results:

• The ionizable lipid 113-AA-C8C14 demonstrated spleen-specific mRNA delivery, achieving a 57-fold enhancement compared to a benchmark LNP.
• LNPs formulated with 113-AA-C8C14 generated 2.7 times more CAR T cells in vivo, leading to increased secretion of IFN-γ and TNF-α.
• This LNP-mediated CAR T cell therapy resulted in a 2.3-fold greater inhibition of tumor growth in a pancreatic cancer mouse model.

Conclusions:

• The novel ionizable lipid 113-AA-C8C14 represents a significant advancement in LNP technology for in vivo gene delivery.
• This LNP formulation enhances CAR T cell generation and efficacy, showing potential for treating various diseases, including cancer.
• The study highlights the potential of 113-AA-C8C14 LNPs for future in vivo CAR T cell therapies.