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
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DOI：
10.1016/j.jconrel.2021.01.005
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发表时间：
2021-01-14
影响因子：
10.8
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Kimura, Seigo;Khalil, Ikramy A.;Harashima, Hideyoshi
本研究报告了一种新型脂质组合的发展，该组合允许质粒DNA （pDNA）高效和高选择性地递送到脾脏中的免疫细胞。使用DODAP，一种以前被认为对基因传递效率低的可电离脂质，我们首次表明，这种被忽视的脂质可以成功地用于体内有效和靶向的基因传递，但只有当与DOPE（一种特定的辅助脂质）结合时。使用一定的DODAP和DOPE比例可以形成脂质纳米颗粒（LNPs），其基因表达量高达1000倍，并且这种表达对脾脏具有特异性，使其成为使用pDNA转染的最具脾脏选择性的系统。发育的DODAP/DOPE-LNPs通过补体C3受体靶向脾脏免疫细胞，这一途径对有效的基因表达至关重要。我们假设DODAP/DOPE-LNPs的高脾转染活性是通过补体受体促进与B细胞活化相关的基因表达引起的。LNPs包封肿瘤抗原编码pDNA，具有预防和治疗双重抗肿瘤作用。优化后的LNPs可产生不同的细胞因子和抗原特异性抗体，并发挥抗原特异性的细胞毒作用。这项研究恢复了DODAP在基因传递中的使用，并强调了使用适当的脂质组合将基因传递到特定细胞的重要性。
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 similar to 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.