An optimized ionizable cationic lipid for brain tumor-targeted siRNA delivery and glioblastoma immunotherapy

  • Biomaterials. 2022 Aug:287:121645. doi: 10.1016/j.biomaterials.2022.121645.
Shuhan Liu  1 ,  Ji Liu  2 ,  Haisong Li  3 ,  Kuirong Mao  4 ,  Haorui Wang  5 ,  Xiandi Meng  5 ,  Jialiang Wang  5 ,  Chenxi Wu  6 ,  Hongmei Chen  5 ,  Xin Wang  5 ,  Xiuxiu Cong  5 ,  Yue Hou  5 ,  Ye Wang  5 ,  Ming Wang  7 ,  Yong-Guang Yang  8 ,  Tianmeng Sun  9
Affiliations
  • 1. Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China; Cancer Center, The First Hospital, Jilin University, Changchun, Jilin, China.
  • 2. Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences (ICCAS), Beijing, China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 3. Department of Neurosurgery, The First Hospital, Jilin University, Changchun, Jilin, China.
  • 4. Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China.
  • 5. Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China.
  • 6. Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China.
  • 7. Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences (ICCAS), Beijing, China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: [email protected].
  • 8. Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. Electronic address: [email protected].
  • 9. Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China; State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, Jilin, China. Electronic address: [email protected].
PMID: 35779480 DOI: 10.1016/j.biomaterials.2022.121645
Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a high mortality rate. Immunotherapy has achieved promising clinical results in multiple cancers, but shows unsatisfactory outcome in GBM patients, and poor drug delivery across the blood-brain barrier (BBB) is believed to be one of the main limitations that hinder the therapeutic efficacy of drugs. Herein, a new cationic lipid nanoparticle (LNP) that can efficiently deliver siRNA across BBB and target mouse brain is prepared for modulating the tumor microenvironment for GBM immunotherapy. By designing and screening cationic LNPs with different ionizable amine headgroups, a lipid (named as BAMPA-O16B) is identified with an optimal acid dissociation constant (PKA) that significantly enhances the cellular uptake and endosomal escape of siRNA lipoplex in mouse GBM cells. Importantly, BAMPA-O16B/siRNA lipoplex is highly effective to deliver siRNA against CD47 and PD-L1 across the BBB into cranial GBM in mice, and downregulate target gene expression in the tumor, resulting in synergistically activating a T cell-dependent antitumor immunity in orthotopic GBM. Collectively, this study offers an effective strategy for brain targeted siRNA delivery and gene silencing by optimizing the physicochemical property of LNPs. The effectiveness of modulating immune environment of GBM could further be expanded for potential treatment of Other brain tumors.

Keywords
Blood-brain barrier; Cationic lipid nanoparticle; Glioblastoma multiforme; Tumor immunotherapy; Tumor microenvironment.
Products