<br>调节 DNA 与球形核酸的解离以增强免疫刺激,ACS Nano

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调节 DNA 与球形核酸的解离以增强免疫刺激
ACS Nano ( IF 15.8 ) Pub Date : 2023-09-15 , DOI: 10.1021/acsnano.3c04333
Jasper W Dittmar ₁ , Michelle H Teplensky ₂ , Michael Evangelopoulos ₁ , Lei Qin ₃ , Bin Zhang ₃ , Chad A Mirkin _{1,

2}

Affiliation

核心的稳定性可以显着影响脂质体药物的治疗效果。虽然球形核酸 (SNA) 结构提高了脂质体稳定性以提高治疗功效，但用于将 DNA 锚定到脂质体核心的化学物质是一个尚未充分研究的设计参数，具有潜在广泛的生物学影响。在此，我们通过系统研究疏水性十二烷锚定基团在将 DNA 链附着到脂质体核心方面的重要性，探讨了 SNA 锚定化学对免疫治疗功能的影响。通过有意调节定义锚定的寡聚物的大小，建立了结构库。这些结构与体外和体内免疫刺激分析相结合，阐明了 DNA 与 SNA 壳的锚定强度和解离对其生物学特性之间的关系和重要性。重要的是，最稳定的十二烷锚定物 (C12) ₉优于n = 4-8 和 10 结构，与传统的胆固醇锚定 SNA 相比，免疫刺激增加了四倍。当 OVA1 肽抗原被 (C12) ₉ SNA 封装并用作 E.G7-OVA 肿瘤模型中的治疗性疫苗时，50% 的小鼠在最初的肿瘤中存活下来，并且所有这些小鼠都在肿瘤再攻击中存活下来。重要的是，与线性免疫刺激DNA相比，强烈的先天免疫刺激不会引起细胞因子风暴。此外，封装了针对 SARS-CoV-2 的肽的 (C12) ₉ SNA 会产生强大的 T 细胞反应； SNA 处理产生的 T 细胞可杀死 >40% 的用相同肽脉冲的靶细胞，并且约 10%。45% 的靶细胞表达整个刺突蛋白。这项工作强调了使用锚定化学来提高 SNA 稳定性的重要性，以在癌症和传染病的背景下实现更有效、更安全的免疫治疗。

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Tuning DNA Dissociation from Spherical Nucleic Acids for Enhanced Immunostimulation

The stability of the core can significantly impact the therapeutic effectiveness of liposome-based drugs. While the spherical nucleic acid (SNA) architecture has elevated liposomal stability to increase therapeutic efficacy, the chemistry used to anchor the DNA to the liposome core is an underexplored design parameter with a potentially widespread biological impact. Herein, we explore the impact of SNA anchoring chemistry on immunotherapeutic function by systematically studying the importance of hydrophobic dodecane anchoring groups in attaching DNA strands to the liposome core. By deliberately modulating the size of the oligomer that defines the anchor, a library of structures has been established. These structures, combined with in vitro and in vivo immune stimulation analyses, elucidate the relationships between and importance of anchoring strength and dissociation of DNA from the SNA shell on its biological properties. Importantly, the most stable dodecane anchor, (C12)₉, is superior to the n = 4–8 and 10 structures and quadruples immune stimulation compared to conventional cholesterol-anchored SNAs. When the OVA1 peptide antigen is encapsulated by the (C12)₉ SNA and used as a therapeutic vaccine in an E.G7-OVA tumor model, 50% of the mice survived the initial tumor, and all of those survived tumor rechallenge. Importantly, the strong innate immune stimulation does not cause a cytokine storm compared to linear immunostimulatory DNA. Moreover, a (C12)₉ SNA that encapsulates a peptide targeting SARS-CoV-2 generates a robust T cell response; T cells raised from SNA treatment kill >40% of target cells pulsed with the same peptide and ca. 45% of target cells expressing the entire spike protein. This work highlights the importance of using anchor chemistry to elevate SNA stability to achieve more potent and safer immunotherapeutics in the context of both cancer and infectious disease.

更新日期：2023-09-15

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