Endotoxicity originating from a dangerous debris (i.e., lipopolysaccharide, LPS) of Gram-negative bacteria is a challenging clinical problem, but no drugs or therapeutic strategies that can successfully address this issue have been identified yet. In this study, we report a subnanometer gold cluster that can efficiently block endotoxin activity to protect against sepsis. The endotoxin blocker consists of a gold nanocluster that serves as a flakelike substrate and a coating of short alkyl motifs that act as an adhesive to dock with LPS by compacting the intramolecular hydrocarbon chain–chain distance (d-spacing) of lipid A, an endotoxicity active site that can cause overwhelming cytokine induction resulting in sepsis progression. Direct evidence showed the d-spacing values of lipid A to be decreased from 4.19 Å to either 3.85 or 3.54 Å, indicating more dense packing densities in the presence of subnanometer gold clusters. In terms of biological relevance, the concentrations of key pro-inflammatory NF-κB-dependent cytokines, including plasma TNF-α, IL-6, and IL-1β, and CXC chemokines, in LPS-challenged mice showed a noticeable decrease. More importantly, we demonstrated that the treatment of antiendotoxin gold nanoclusters significantly prolonged the survival time in LPS-induced septic mice. The ultrasmall gold nanoclusters could target lipid A of LPS to deactivate endotoxicity by compacting its packing density, which might constitute a potential therapeutic strategy for the early prevention of sepsis caused by Gram-negative bacterial infection.

中文翻译：

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亚纳米级金团簇附着在脂质A上，可预防内毒素引起的脓毒症

革兰氏阴性细菌的危险碎片（即脂多糖，LPS）引起的内毒性是一个具有挑战性的临床问题，但是尚未找到能够成功解决该问题的药物或治疗策略。在这项研究中，我们报告了一个亚纳米级的金簇，它可以有效地阻止内毒素的活性，以预防败血症。内毒素阻滞剂由充当薄片状底物的金纳米簇和短烷基基序涂层组成，这些涂层通过压实脂质A的分子内烃链-链距（d间距）而与LPS对接，这是一种内毒素可能导致压倒性细胞因子诱导的活性位点，导致败血症进展。直接的证据表明，d脂质A的-spacing值将从4.19Å降低到3.85或3.54Å，表明在存在亚纳米金簇的情况下堆积密度更高。在生物学相关性方面，LPS攻击的小鼠中关键促炎性NF-κB依赖性细胞因子（包括血浆TNF-α，IL-6和IL-1β和CXC趋化因子）的浓度显着降低。更重要的是，我们证明了抗内毒素金纳米簇的治疗显着延长了LPS诱导的败血症小鼠的存活时间。超小型金纳米簇可以通过压缩脂多糖的堆积密度来靶向脂多糖脂类，从而使内毒素失活，这可能是早期预防革兰氏阴性细菌感染引起败血症的潜在治疗策略。