Impact of Liposomal Spherical Nucleic Acid Structure on Immunotherapeutic Function.
Impact of Liposomal Spherical Nucleic Acid Structure on Immunotherapeutic Function.
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DOI：
10.1021/acscentsci.1c00181
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发表时间：
2021-05-26
影响因子：
18.2
通讯作者：
Mirkin CA
中科院分区：
文献类型：
--
作者：
Callmann CE;Kusmierz CD;Dittmar JW;Broger L;Mirkin CA
脂质体球形核酸(L-SNAs)在肿瘤免疫治疗中显示出重要的应用前景。L-RNA是高度模块化的纳米级组件，由脂质体核心周围密集、直立的寡核苷酸径向排列定义。在这里，我们通过研究L-RNA的生物学和免疫学性质作为脂质体组成的函数，建立了一套L-RNA的设计规则。为了实现这一目标，我们用1，2-二油酰磷脂酰胆碱(DOPC)、1，2-二肉豆蔻酰磷脂酰胆碱(DMPC)、1，2-二棕榈酰磷脂酰胆碱(DPPC)或1，2-二硬脂酰磷脂酰胆碱(DSPC)合成了脂质体，其中磷脂酰胆碱的头部基团保持不变，而双脂酰磷脂酰胆碱的尾链长度和饱和度不同。这些研究表明，组成脂质的一致性决定了L-SNA的DNA载量、细胞摄取、血清稳定性、体外免疫刺激活性和体内淋巴聚集。此外，在4T1小鼠三阴性乳腺癌模型中，与DOPC合成的免疫刺激L RNA相比，DPPC合成的免疫刺激RNA显著减少了肺转移的产生，并延缓了肿瘤的生长，这是因为DPPC合成的L-RNA的稳定性高于DOPC合成的L-RNA。此外，将来源于PY8119TNBC细胞的细胞裂解物作为抗原源包含在L-SNAs中，当裂解物被包裹在用DPPC而不是DOPC合成的L-SNAs的核心时，在PY8119模型中的抗肿瘤效果显著提高，这可能是由于体内增加了佐剂和抗原向树突状细胞的共递送。当使用氧化的PY8119细胞的裂解物作为更有效的抗原源时，这种差异被进一步放大，揭示了裂解物制备方法和脂质体组合物在合成免疫治疗性L-RNA方面的协同作用。综上所述，本工作表明，L-RNA的生物学特性和免疫调节活性可以通过交换脂质体成分来调节，为合理设计纳米级免疫治疗药物提供了另一种手段。构成脂质体球形核酸的脂类的分子同一性调节了它们的生物学特性，并为它们作为癌症免疫治疗药物的合理设计提供了句柄。
Liposomal spherical nucleic acids (L-SNAs) show significant promise as cancer immunotherapeutics. L-SNAs are highly modular nanoscale assemblies defined by a dense, upright radial arrangement of oligonucleotides around a liposomal core. Herein, we establish a set of L-SNA design rules by studying the biological and immunological properties of L-SNAs as a function of liposome composition. To achieve this, we synthesized liposomes where the lipid phosphatidylcholine headgroup was held constant, while the diacyl lipid tail chain length and degree of saturation were varied, using either 1,2-dioleylphosphatidylcholine (DOPC), 1,2-dimyristoyl-phosphatidylcholine (DMPC), 1,2-dipalmitoylphosphatidylcholine (DPPC), or 1,2-distearoyl-phosphatidylcholine (DSPC). These studies show that the identity of the constituent lipid dictates the DNA loading, cellular uptake, serum stability, in vitro immunostimulatory activity, and in vivo lymph node accumulation of the L-SNA. Furthermore, in the 4T1 mouse model of triple-negative breast cancer (TNBC), the subcutaneous administration of immunostimulatory L-SNAs synthesized with DPPC significantly decreases the production of lung metastases and delays tumor growth as compared to L-SNAs synthesized using DOPC, due to the enhanced stability of L-SNAs synthesized with DPPC over those synthesized with DOPC. Moreover, the inclusion of cell lysates derived from Py8119 TNBC cells as antigen sources in L-SNAs leads to a significant increase in antitumor efficacy in the Py8119 model when lysates are encapsulated in the cores of L-SNAs synthesized with DPPC rather than DOPC, presumably due to increased codelivery of adjuvant and antigen to dendritic cells in vivo. This difference is further amplified when using lysates from oxidized Py8119 cells as a more potent antigen source, revealing synergy between the lysate preparation method and liposome composition in synthesizing immunotherapeutic L-SNAs. Together, this work shows that the biological properties and immunomodulatory activity of L-SNAs can be modulated by exchanging liposome components, providing another handle for the rational design of nanoscale immunotherapeutics. The molecular identity of the lipids that comprise liposomal spherical nucleic acids modulates their biological properties and provides a handle for their rational design as cancer immunotherapeutics.
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影响因子：
64.8
作者：
Mirkin, CA;Letsinger, RL;Storhoff, JJ
通讯作者：
Storhoff, JJ
DOI：
10.1073/pnas.2005794117
发表时间：
2020-07-28
影响因子：
11.1
作者：
Callmann, Cassandra E.;Cole, Lisa E.;Mirkin, Chad A.
通讯作者：
Mirkin, Chad A.
影响因子：
8
作者：
Bozzuto G;Molinari A
通讯作者：
Molinari A
整个肿瘤抗原疫苗。
影响因子：
7.8
作者：
Chiang CL;Benencia F;Coukos G
通讯作者：
Coukos G
影响因子：
1.3
作者：
Kheyfets, B.;Galimzyanov, T.;Mukhin, S.
通讯作者：
Mukhin, S.