脂质纳米颗粒上的蛋白冠形成对 NLRP3 炎症小体激活产生负面影响,Bioconjugate Chemistry

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脂质纳米颗粒上的蛋白冠形成对 NLRP3 炎症小体激活产生负面影响
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2023-09-14 , DOI: 10.1021/acs.bioconjchem.3c00329
Maharshi Debnath ₁ , James Forster ₁ , Anujan Ramesh ₂ , Ashish Kulkarni _{1,

2,

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Affiliation

脂质纳米颗粒 (LNP) 和血清蛋白之间的相互作用，以蛋白冠的形式产生独特的识别，已被证明与细胞受体的新识别有关。包围纳米颗粒的电晕的存在强烈影响与免疫细胞的相互作用。由蛋白电晕介导的免疫反应可以影响纳米粒子的毒性和靶向能力。但电晕形成后 LNP 的细胞内信号传导导致纳米颗粒激发免疫反应的能力发生变化，目前尚不清楚。因此，必须考虑采用更系统和更明确的方法来呈现电晕复合物与纳米颗粒免疫原性变化之间的相关性。在这里，我们研究并报道了 LNP 上吸收的蛋白对 NLRP3 炎症小体激活的抑制作用，NLRP3 炎症小体是调节多种炎症反应的关键细胞内蛋白复合物。据观察，可电离脂质作为 LNP 的组成部分，在无血清条件下调节 NLRP3 炎症小体的激活中发挥重要作用。然而，在血清蛋白存在的情况下，LNP 上的冠层导致炎症小体激活显着减少。Corona-LNP 治疗后溶酶体破裂的减少显着减少了炎症小体的激活。此外，观察到冠形成后巨噬细胞的细胞摄取急剧减少。在使用转运抑制剂检查巨噬细胞的摄取机制时，发现脂质制剂在确定巨噬细胞中 LNP 的内吞途径中发挥着关键作用。这项研究强调需要批判性地分析蛋白质与纳米材料的相互作用及其与免疫细胞的适应性，以评估纳米生物表面并成功设计用于生物应用的纳米材料。

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Protein Corona Formation on Lipid Nanoparticles Negatively Affects the NLRP3 Inflammasome Activation

The interaction between lipid nanoparticles (LNPs) and serum proteins, giving rise to a unique identification in the form of the protein corona, has been shown to be associated with novel recognition by cell receptors. The presence of the corona enveloping the nanoparticle strongly affects the interplay with immune cells. The immune responses mediated by protein corona can affect nanoparticle toxicity and targeting capabilities. But the intracellular signaling of LNPs after corona formation resulting in the change of nanoparticles’ ability to provoke immune responses remains unclear. Therefore, a more systematic and delineated approach must be considered to present the correlation between corona complexes and the shift in nanoparticle immunogenicity. Here, we studied and reported the inhibiting effect of the absorbed proteins on the LNPs on the NLRP3 inflammasome activation, a key intracellular protein complex that modulates several inflammatory responses. Ionizable lipid as a component of LNP was observed to play an important role in modulating the activation of NLRP3 inflammasome in serum-free conditions. However, in the presence of serum proteins, the corona layer on LNPs caused a significant reduction in the inflammasome activation. Reduction in the lysosomal rupture after treatment with corona-LNPs significantly reduced inflammasome activation. Furthermore, a strong reduction of cellular uptake in macrophages after the corona formation was observed. On inspecting the uptake mechanisms in macrophages using transport inhibitors, lipid formulation was found to play a critical role in determining the endocytic pathways for the LNPs in macrophages. This study highlights the need to critically analyze the protein interactions with nanomaterials and their concomitant adaptability with immune cells to evaluate nano–bio surfaces and successfully design nanomaterials for biological applications.

更新日期：2023-09-14

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