Nanoparticle-mediated co-delivery of inflammasome inhibitors provides protection against sepsis
Nanoparticle-mediated co-delivery of inflammasome inhibitors provides protection against sepsis
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DOI：
10.1039/d3nr05570a
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发表时间：
2024-01-10
期刊：
影响因子：
6.7
通讯作者：
Kulkarni，Ashish
中科院分区：
文献类型：
--
作者：
Nandi，Dipika;Debnath，Maharshi;Kulkarni，Ashish
NLRP 3炎性体是一种多蛋白复合物，负责触发促炎细胞因子的释放，在诱导脓毒症相关的炎症反应中起着至关重要的作用。虽然已经研究了NLRP 3炎性体的小分子抑制剂用于脓毒症管理，但递送NLRP 3抑制剂伴随着几个挑战，主要涉及药物制剂、递送途径、稳定性和毒性。许多现有的炎性小体抑制剂显示出较高的肝毒性或需要高剂量以有效地阻止炎性小体复合物组装。此外，在脓毒症治疗中组合多种炎性体抑制剂的潜在协同作用仍然在很大程度上未被探索。因此，合理的方法对于呈现NLRP 3小分子抑制剂的潜在施用以有效抑制NLRP 3炎性体活化是至关重要的。在这种情况下，我们提出了一种基于脂质纳米颗粒的双药物递送系统与MCC 950和双硫仑装载，表现出显着更高的效率相比，等量的游离药物组合和单独的药物纳米颗粒在体外。这种联合治疗显著提高了LPS诱导的脓毒性腹膜炎小鼠的体内存活率。此外，协同方法表明NLRP 3途径中活性半胱天冬酶-1以及IL-1 β抑制积分组分的表达显著降低。这项研究强调了通过纳米颗粒递送促进整合联合治疗以解决小分子炎性体抑制剂的局限性的重要性。
The NLRP3 inflammasome, a multiprotein complex responsible for triggering the release of pro-inflammatory cytokines, plays a crucial role in inducing the inflammatory response associated with sepsis. While small molecule inhibitors of the NLRP3 inflammasome have been investigated for sepsis management, delivering NLRP3 inhibitors has been accompanied by several challenges, primarily related to the drug formulation, delivery route, stability, and toxicity. Many existing inflammasome inhibitors either show higher liver toxicity or require a high dosage to efficiently impede the inflammasome complex assembly. Moreover, the potential synergistic effects of combining multiple inflammasome inhibitors in sepsis therapy remain largely unexplored. Therefore, a rational approach is essential for presenting the potential administration of NLRP3 small molecule inhibitors to inhibit NLRP3 inflammasome activation effectively. In this context, we present a lipid nanoparticle-based dual-drug delivery system loaded with MCC 950 and disulfiram, demonstrating markedly higher efficiency compared to an equivalent amount of free-drug combinations and individual drug nanoparticles in vitro. This combination therapy substantially improved the in vivo survival rate of mice for LPS-induced septic peritonitis. Additionally, the synergistic approach illustrated a significant reduction in the expression of active caspase-1 as well as IL-1β inhibition integral components in the NLRP3 pathway. This study underscores the importance of integrating combination therapies facilitated by nanoparticle delivery to address the limitations of small molecule inflammasome inhibitors.