Protein Corona Formation on Lipid Nanoparticles Negatively Affects the NLRP3 Inflammasome Activation
Protein Corona Formation on Lipid Nanoparticles Negatively Affects the NLRP3 Inflammasome Activation
复制标题
DOI：
10.1021/acs.bioconjchem.3c00329
复制
发表时间：
2023-09-14
影响因子：
4.7
通讯作者：
Kulkarni，Ashish
中科院分区：
文献类型：
--
作者：
Debnath，Maharshi;Forster，James;Kulkarni，Ashish
脂质纳米颗粒（LNPs）与血清蛋白之间的相互作用，以蛋白质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。包裹纳米颗粒的电晕的存在强烈地影响了与免疫细胞的相互作用。蛋白冠介导的免疫反应可影响纳米颗粒的毒性和靶向能力。但LNPs在冠状形成后的细胞内信号传导导致纳米颗粒引发免疫反应能力的改变尚不清楚。因此，必须考虑一种更系统和更明确的方法来呈现冠状复合物与纳米颗粒免疫原性转移之间的相关性。在这里，我们研究并报道了LNPs上吸收的蛋白质对NLRP3炎性小体激活的抑制作用，NLRP3是调节几种炎症反应的关键细胞内蛋白复合物。可电离脂质作为LNP的一个组成部分在无血清条件下调节NLRP3炎性体的激活中发挥重要作用。然而，在血清蛋白存在的情况下，LNPs上的冠层导致炎性体激活的显著降低。冠状病毒lnps治疗后溶酶体破裂的减少显著降低了炎性体的活化。此外，观察到巨噬细胞在冠状形成后细胞摄取的强烈减少。在使用转运抑制剂检查巨噬细胞的摄取机制时，发现脂质形成在决定巨噬细胞LNPs的内吞途径中起关键作用。本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伴随适应性，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。
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.