Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)–poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151–as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/STING-driven inflammatory conditions.

中文翻译：

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STING 通路抑制纳米颗粒 (SPIN) 作为治疗炎症疾病的平台

环 GMP-AMP 合酶 (cGAS)/干扰素基因刺激物 (STING) 通路的异常激活与多种炎症性疾病的发生和进展有关，包括结肠炎、非酒精性脂肪性肝炎、肌萎缩侧索硬化症 (ALS) 和年龄相关黄斑变性。因此，STING 通路抑制剂可以在许多炎症性疾病中具有治疗应用。 cGAS 抑制剂 RU.521 和 STING 抑制剂 H-151 已显示出作为结肠炎、ALS 等小鼠模型的治疗药物的前景。然而，这些药物需要频繁的高剂量腹腔注射，这可能会限制可转化性。此外，长期全身使用 cGAS/STING 抑制剂可能会使患者容易受到病毒感染和癌症的影响。因此，cGAS/STING 通路的局部或靶向抑制可能是一种有吸引力的、广泛适用的治疗多种 STING 通路驱动疾病的方法。在这里，我们描述了 STING 通路抑制纳米颗粒 (SPINS)——负载有 RU.521 和 H-151 的聚乳酸乙醇酸 (PLGA) 纳米颗粒——作为增强和持续抑制 cGAS/STING 信号传导的平台。我们证明，SPIN 在抑制胞质 DNA 诱导的 I 型干扰素反应方面与游离 H-151 或 RU.521 同等或更有效。此外，我们还描述了一种 SPIN 配方，其中 PLGA 与聚（苯甲酰氧基丙基甲基丙烯酰胺）（P(HPMA-Bz)）共乳化，可显着提高载药量，并允许在数天至一周以上的时间内调节 H-151 的释放通过改变 P(HPMA-Bz) 含量。最后，我们发现所有 SPIN 制剂在抑制原代小鼠巨噬细胞中的 cGAS/STING 信号传导方面均有效或更有效，导致炎症 M1 样巨噬细胞标志物的表达减少。因此，我们的研究为 STING 通路抑制剂的纳米粒子递送提供了体外概念验证，并将 SPIN 定位为减缓或逆转 cGAS/STING 驱动的炎症状况的发作或进展的潜在平台。