Nucleic acid (NA)-containing damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) are implicated in numerous pathological conditions from infectious diseases to autoimmune disorders. Nucleic acid-binding polymers, including polyamidoamine (PAMAM) dendrimers, have demonstrated anti-inflammatory properties when administered to neutralize DAMPs/PAMPs. The PAMAM G3 variant has been shown to have beneficial effects in a cutaneous lupus erythematosus (CLE) murine model and improve survival of mice challenged with influenza. Unfortunately, the narrow therapeutic window of cationic PAMAM dendrimers makes their clinical development challenging. An alternative nucleic acid-binding polymer that has been evaluated in humans is a linear β-cyclodextrin-containing polymer (CDP). CDP’s characteristics prompted us to evaluate its anti-inflammatory potential in CLE autoimmune and influenza infectious disease mouse models. We report that CDP effectively inhibits NA-containing DAMP-mediated activation of Toll-like receptors (TLRs) in cell culture, improves healing in lupus mice, and does not immunocompromise treated animals upon influenza infection but improves survival even when administered 3 days after infection. Finally, as anticipated, we observe limited toxicity in animals treated with CDP compared with PAMAM G3. Thus, CDP is a new anti-inflammatory agent that may be readily translated to the clinic to combat diseases associated with pathological NA-containing DAMPs/PAMPs.

含有核酸 (NA) 的损伤相关分子模式和病原体相关分子模式（分别为 DAMP 和 PAMP）与从传染病到自身免疫性疾病的多种病理状况有关。核酸结合聚合物，包括聚酰胺胺 (PAMAM) 树枝状聚合物，在中和 DAMP/PAMP 时已表现出抗炎特性。 PAMAM G3 变体已被证明对皮肤红斑狼疮 (CLE) 小鼠模型具有有益作用，并可提高遭受流感攻击的小鼠的存活率。不幸的是，阳离子 PAMAM 树枝状聚合物的治疗窗口狭窄，使其临床开发充满挑战。已在人体中进行评估的另一种核酸结合聚合物是线性含 β-环糊精的聚合物 (CDP)。 CDP 的特性促使我们评估其在 CLE 自身免疫和流感传染病小鼠模型中的抗炎潜力。我们报告说，CDP 可有效抑制细胞培养物中含有 NA 的 DAMP 介导的 Toll 样受体 (TLR) 的激活，改善狼疮小鼠的愈合，并且在感染流感后不会使接受治疗的动物免疫受损，但即使在感染后 3 天给药，也能提高存活率。最后，正如预期的那样，与 PAMAM G3 相比，我们观察到用 CDP 治疗的动物的毒性有限。因此，CDP是一种新的抗炎剂，可以很容易地转化为临床以对抗与含有病理性NA的DAMP/PAMP相关的疾病。