2. Academic Validation
  3. Esterase-Labile Quaternium Lipidoid Enabling Improved mRNA-LNP Stability and Spleen-Selective mRNA Transfection

Esterase-Labile Quaternium Lipidoid Enabling Improved mRNA-LNP Stability and Spleen-Selective mRNA Transfection

  • Adv Mater. 2023 Nov;35(46):e2303614. doi: 10.1002/adma.202303614.
Runnan Zhang 1 2,  Shiqun Shao 1 2 3,  Ying Piao 1 2,  Jiajia Xiang 1 2,  Xuyong Wei 4 5,  Zhen Zhang 6,  Zhuxian Zhou 1 2,  Jianbin Tang 1 2,  Nasha Qiu 4 5,  Xiao Xu 7 5,  Yanpeng Liu 4 5,  Youqing Shen 1 2
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310058, China.
  • 2 Key Laboratory of Biomass Chemical Engineering of the Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310058, China.
  • 3 ZJU-Hangzhou Global Scientific and Technological Innovation Center, 311215, Hangzhou, China.
  • 4 The Center for Integrated Oncology and Precision Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
  • 5 Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China.
  • 6 Zhejiang Longcharm Bio-tech Pharma Co., Ltd., Hangzhou, 310018, China.
  • 7 Zhejiang University School of Medicine, Hangzhou, 310058, China.
PMID: 37490011 DOI: 10.1002/adma.202303614
Abstract

Ionizable Cationic Lipids are recognized as an essential component of lipid nanoparticles (LNPs) for messenger RNA (mRNA) delivery but can be confounded by low lipoplex stability with mRNA during storage and in vivo delivery. Herein, the rational design and combinatorial synthesis of esterase-triggered decationizable quaternium lipid-like molecules (lipidoids) are reported to develop new LNPs with high delivery efficiency and improved storage stability. This top lipidoid carries positive charges at the physiological condition but promptly acquires negative charges in the presence of esterase, thus permitting stable mRNA encapsulation during storage and in vivo delivery while balancing efficient mRNA release in the cytosol. An optimal LNP formulation is then identified through orthogonal optimization, which enables efficacious mRNA transfection selectively in the spleen following intravenous administration. LNP-mediated delivery of ovalbumin (OVA)-encoding mRNA induces efficient antigen expression in antigen-presenting cells and elicits robust antigen-specific immune responses against OVA-transduced tumors. The work demonstrates the potential of decationizable quaternium lipidoids for spleen-selective RNA transfection and Cancer Immunotherapy.

Keywords

messenger RNA; quaternium lipidoids; spleen-specific transfection; stability; tumor immunotherapy.

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