1. Academic Validation
  2. Novel lipid combination for delivery of plasmid DNA to immune cells in the spleen

Novel lipid combination for delivery of plasmid DNA to immune cells in the spleen

  • J Control Release. 2021 Feb 10;330:753-764. doi: 10.1016/j.jconrel.2021.01.005.
Seigo Kimura 1 Ikramy A Khalil 2 Yaser H A Elewa 3 Hideyoshi Harashima 4
Affiliations

Affiliations

  • 1 Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
  • 2 Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: ikramy@aun.edu.eg.
  • 3 Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt; Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan.
  • 4 Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Laboratory for Molecular Design of Pharmaceuticsx, Department of Biomedical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
Abstract

This study reports on the development of a novel lipid combination that permits the efficient and highly selective delivery of plasmid DNA (pDNA) to immune cells in the spleen. Using DODAP, an ionizable lipid that was previously thought to be inefficient for gene delivery, we show for the first time, that this ignored lipid can be successfully used for efficient and targeted gene delivery in vivo, but only when combined with DOPE, a specific helper lipid. Using certain DODAP and DOPE ratios resulted in the formation of lipid nanoparticles (LNPs) with a ~ 1000-fold higher gene expression, and this expression was specific for the spleen, making it the most spleen-selective system for transfection using pDNA. The developed DODAP/DOPE-LNPs target immune cells in the spleen via receptors for complement C3 and this pathway is critical for efficient gene expression. We hypothesize that the high spleen transfection activity of DODAP/DOPE-LNPs is caused by the promotion of gene expression associated with B cell activation via complement receptors. LNPs encapsulating tumor-antigen encoding pDNA showed both prophylactic and therapeutic anti-tumor effects. The optimized LNPs resulted in the production of different cytokines and antigen-specific Antibodies as well as exerting antigen-specific cytotoxic effects. This study revives the use of DODAP in gene delivery and highlights the importance of using appropriate lipid combinations for delivering genes to specific cells.

Keywords

Immune cell; Ionizable lipid; Nanoparticle; Plasmid; Spleen; Vaccine.

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