负载 p65 siRNA 的丁福明/DNA 纳米棱柱通过抑制 NLRP3 介导的细胞焦亡减轻急性肺损伤,ACS Applied Nano Materials

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负载 p65 siRNA 的丁福明/DNA 纳米棱柱通过抑制 NLRP3 介导的细胞焦亡减轻急性肺损伤
ACS Applied Nano Materials ( IF 5.3 ) Pub Date : 2023-10-26 , DOI: 10.1021/acsanm.3c03893
Qianyi You ₁ , Qiao Hu ₂ , Chaowang Huang ₂ , Jing Xu ₂ , Yawen Guo ₂ , Dan Wang ₂ , Xiaolong Chen ₂ , Hang Qian ₁ , Mingdong Hu ₂

Affiliation

急性肺损伤（ALI）和急性呼吸窘迫综合征由复杂的分子机制引发，是危重患者高死亡率的主要原因。最近的研究表明，细胞焦亡导致高水平 IL-1β 和 IL-18 的释放，在引起细胞因子风暴、导致严重呼吸损伤的过程中发挥着关键作用。DNA纳米结构具有生物相容性、可编程性、生物降解性和无毒性等理想特性，使其适合用作药物输送载体。在这项研究中，发现DNA纳米棱柱作为传递丁双胍的载体，丁双胍不仅作为DNA组装的介质，而且还是抑制NOD样受体家族pyrin结构域3（NLRP3）的药物-介导的细胞焦亡。为了增强丁福明的治疗效果，将六个 p65 siRNA 分子装载到 DNA 纳米棱柱上。丁福明和 p65 siRNA 均表现出对 NLRP3 介导的细胞焦亡的显着抑制作用。此外，在体外巨噬细胞焦亡模型和ALI小鼠体内模型中研究了负载p65 siRNA的丁福明/DNA纳米棱柱通过抑制细胞焦亡来降低炎症水平的协同效应。总之，这种DNA纳米平台有可能改变未来ALI的治疗方法，因为它同时携带两种治疗药物，产生协同治疗效果。这种提出的方法提供了可以提高 ALI 治疗整体有效性的新策略。

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p65 siRNA-Loaded Buformin/DNA Nanoprisms Alleviate Acute Lung Injury through Inhibiting NLRP3-Mediated Pyroptosis

Acute lung injury (ALI) and acute respiratory distress syndrome are triggered by complicated molecular mechanisms, which are the prime causes of high mortality in critical patients. Recent research suggests that the release of high levels of IL-1β and IL-18, resulting from pyroptosis, plays a pivotal role in causing cytokine storms that lead to severe respiratory damage. DNA nanostructures possess desirable properties, such as biocompatibility, programmability, biodegradability, and nontoxicity, making them suitable for use as drug delivery vehicles. In this study, it has been found that the DNA nanoprism acts as a carrier to deliver buformin, which serves as not only a mediator for DNA assembly but also a drug that inhibits NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis. To enhance the therapeutic effect of buformin, six p65 siRNA molecules are loaded onto the DNA nanoprism. Both buformin and p65 siRNA demonstrated remarkable inhibition of NLRP3-mediated pyroptosis. Furthermore, the synergistic effect of the p65 siRNA-loaded buformin/DNA nanoprism in reducing inflammation levels by inhibiting pyroptosis was investigated in both an in vitro model of macrophage cell pyroptosis and an in vivo model of ALI mice. In conclusion, this DNA nanoplatform has the potential to change the future treatment of ALI as it carries two therapeutic agents simultaneously, resulting in synergistic therapeutic effects. This proposed approach offers new strategies that could enhance the overall effectiveness of the ALI treatment.

更新日期：2023-10-26

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