Subnanometer Gold Clusters Adhere to Lipid A for Protection against Endotoxin-Induced Sepsis

Abstract

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.

Antibiotic‐Free Antibacterial Strategies Enabled by Nanomaterials: Progress and Perspectives

“…Copyright 2015, American Chemical Society. (c,d) Reproduced with permission . Copyright 2018, American Chemical Society.…”

“…Lin and co‐workers reported a strategy using sub‐nanometer gold clusters (SAuNCs) to block the endotoxin activity of LPS and prolong the survival time of mice with LPS‐induced sepsis (Figure c,d). The gold nanoclusters modified with alkyl groups increased the density of the lipid A domain of LPS, hindering LPS recognition by toll‐like receptor 4 for inflammation activation …”

“…Nanomaterials have a large variety of compositions and thus offer a number of unique advantages. First, the physiochemical properties of nanomaterials, such as size, surface chemistry, and shape, can be precisely controlled, leading to functional materials with intrinsic antibacterial activity through cell membrane damage or nutrient starvation, light‐assisted antibacterial activity, and immunomodulation . Second, nanomaterials can act as delivery vehicles to facilitate the permeability, controlled release, and targeted bacterial uptake of natural compounds and improve their stability for bacterial inhibition or as adjuvants in vaccine formulations, thus improving the potency with reduced dosage .…”

The Bioactive Core and Corona Synergism of Quantized Gold Enables Slowed Inflammation and Increased Tissue Regeneration in Wound Hypoxia

“…The synthesis of QG has previously been reported elsewhere [43,44]. The gold-modified PSMA nanofibers were fabricated using the following procedures.…”

“…Then the cells were incubated in an incubator with 1% O 2 for up to 1 day. The HDFs were then harvested and centrifuged for 1 min at 4 • C. The experimental protocol that was followed was similar to the protocol described previously [43]. The cells were lysed with RIPA buffer with halt protease and phosphatase inhibitor cocktail.…”