核心稳定性对脂质体药物的治疗效果有重要影响。而球形核酸（SNA）结构将脂质体稳定性提升至增加治疗效力，DNA与脂质体核心连接的化学反应是一个尚未充分探索的设计参数，具有潜在广泛的生物影响。本研究旨在系统研究亲疏水十二烷锚定基在连接DNA链与脂质体核心中的重要性，以探究其对免疫治疗功能的影响。通过有意调节定义锚定关系的寡聚物大小，建立了一个结构库。这些结构与体外和体内的免疫刺激分析相结合，阐明了锚定强度和DNA与SNA壳层之间的解离对其生物性质的关系和重要性。重要的是，最稳定的十二烷锚定基（C12）9优于n = 4-8和10结构，并且与常规胆固醇锚定的SNA相比，免疫刺激性增强四倍。当OVA1肽抗原被（C12）9 SNA封装并用作E.G7-OVA肿瘤模型的治疗疫苗时，50%的小鼠存活了初始肿瘤，并且所有这些小鼠经受住了肿瘤再次挑战。重要的是，强烈的先天免疫刺激与线性免疫刺激DNA相比不会引起细胞因子风暴。此外，（C12）9 SNA能够封装针对SARS-CoV-2的肽产生强大的T细胞反应；通过SNA处理产生的T细胞能够杀死同一肽脉冲的靶细胞的>40％以及表达整个刺突蛋白的目标细胞的约45％。这项工作突出了使用锚定化学反应提高SNA稳定性的重要性，以在癌症和传染病两个背景下获得更有效且更安全的免疫治疗。

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.