Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts 01003, United States.
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003, United States.
ACS Appl Mater Interfaces. 2023 Dec 6;15(48):55545-55558. doi: 10.1021/acsami.3c15733. Epub 2023 Nov 22.
Inflammasomes are multimeric protein signaling complexes that are assembled in innate immune cells in response to a multitude of pathogen and damage-associated signals. They are essential for generating robust inflammatory responses to prevent pathogenic insults. However, inflammasome dysregulation can induce cascading immune responses, resulting in systemic toxicities and inflammatory disease. In this sense, there is a strong need to develop potent inflammasome inhibiting therapies as well as technologies to monitor their efficacy, yet current systems lack the ability to effectively image inflammasome activation and track therapy response early. To overcome these limitations, we report a novel nanoparticle system delivering both a caspase-1 cleavable inflammasome detecting probe and the NLRP3 inhibitor drug MCC-950, providing dual capabilities of monitoring and regulation of inflammasome activation in a biocompatible, tissue penetrating, and sustained release liposomal formulation. We observed this liposomal nanoreporter's ability to reduce and detect inflammasome activation both in immortalized bone marrow-derived macrophages and in a DSS-induced ulcerative colitis mouse model. Our results exhibited the nanoreporter's ability to penetrate inflammatory tissues and detect inflammasome activation early and in real-time for multiple days while alleviating inflammation in the groups coencapsulating imaging reporter and inflammasome inhibitor. Overall, the developed liposomal nanoreporter platform enables spatiotemporal delivery of imaging probe and inhibitor, captures early and sustained inflammasome detection, and induces inflammasome amelioration, thus establishing a novel tool for the real-time monitoring and treatment of inflammasome-mediated disease with high potential for clinical application.
炎症小体是一种多聚体蛋白信号复合物，在先天免疫细胞中组装，以响应多种病原体和损伤相关信号。它们对于产生强大的炎症反应以防止病原体侵袭至关重要。然而，炎症小体失调会引发级联免疫反应，导致全身毒性和炎症性疾病。从这个意义上说，强烈需要开发有效的炎症小体抑制疗法以及监测其疗效的技术，而目前的系统缺乏有效成像炎症小体激活和早期跟踪治疗反应的能力。为了克服这些限制，我们报告了一种新型纳米颗粒系统，该系统同时输送一种 caspase-1 可切割的炎症小体检测探针和 NLRP3 抑制剂药物 MCC-950，提供了在生物相容、组织穿透和持续释放脂质体配方中监测和调节炎症小体激活的双重能力。我们观察到这种脂质体纳米报告器能够减少和检测在永生化骨髓来源的巨噬细胞中和 DSS 诱导的溃疡性结肠炎小鼠模型中的炎症小体激活。我们的结果显示了纳米报告器穿透炎症组织并早期实时检测炎症小体激活的能力，持续多天，同时减轻了共封装成像报告器和炎症小体抑制剂的组中的炎症。总体而言，开发的脂质体纳米报告器平台能够实现成像探针和抑制剂的时空递药，捕捉早期和持续的炎症小体检测，并诱导炎症小体改善，从而为实时监测和治疗炎症小体介导的疾病提供了一种新的工具，具有很高的临床应用潜力。
