Department of Chemical Engineering, University of Massachusetts, Amherst, MA 01003, USA.
Department of Pathology, UMass Chan Medical School-Baystate, Springfield, MA 01107, USA.
Biomater Sci. 2024 Sep 10;12(18):4790-4805. doi: 10.1039/d4bm00580e.
Understanding the interactions of nanoparticle carriers with innate immune cells is crucial for informing the design and efficacy of future nano-immunotherapies. An intriguing aspect of their interaction with the immune system has recently emerged, , their ability to activate the NLRP3 inflammasome, a key component of the innate immune response. While the effect of the surface properties of nanoparticles has been extensively investigated in the context of nanoparticle-immune cell interactions, the influence of core composition remains largely unexplored, particularly regarding its impact on inflammasome activation. To shed light on these interactions, we developed a library of supramolecular polymer nanoparticles (SNPs) with different core compositions, varying their hydrophobic quotient by virtue of the side chain length and the repeating units in the polymer construct. The impact of modulating SNP core hydrophobic properties was investigated in macrophages by evaluating their cellular internalization, cytokine release, lysosomal rupture-calcium signaling, calcium flux-mitochondrial ROS production and their ability to activate the NLRP3 inflammasome, providing mechanistic insights into inflammasome activation. We established a direct correlation between increasing the side chain length of the polymer construct, thereby increasing the core hydrophobicity of SNPs and enhanced NLRP3 complex formation, as indicated by ASC speck imaging analysis and the elevated 1L-1β expression. Furthermore, the results demonstrated that the inflammasome signaling cascades and kinetics varied based on the SNP's hydrophobic side chain length and repeating units. Specifically, the nanoparticle with the longest alkyl side chain effectuated NLRP3 activation preferentially through the mitochondrial damage pathway. evaluation of SNPs in C57BL/6 mice confirmed elevated proinflammatory cytokines, notably with the SNP having the longest C-alkyl side chain. This confirms that the higher core hydrophobicity composition of the SNP results in inflammasome activation . In summary, this study established SNP core composition as a novel nanoparticle-associated molecular pattern (NAMP) responsible for NLRP3 inflammasome activation, shedding light on intricate cellular pathways for informed nanoparticle design in immunotherapy and vaccine applications.
了解纳米载体与固有免疫细胞的相互作用对于为未来的纳米免疫治疗提供设计和疗效信息至关重要。最近，它们与免疫系统相互作用的一个有趣方面已经显现出来，即它们激活 NLRP3 炎性体的能力，这是先天免疫反应的关键组成部分。虽然纳米颗粒的表面特性在纳米颗粒-免疫细胞相互作用的背景下已经得到了广泛的研究，但核心成分的影响在很大程度上仍未得到探索，特别是关于其对炎性体激活的影响。为了阐明这些相互作用，我们开发了一系列具有不同核心组成的超分子聚合物纳米颗粒（SNP），通过聚合物结构中侧链长度和重复单元的变化来改变其疏水性商。通过评估巨噬细胞中的细胞内吞作用、细胞因子释放、溶酶体破裂-钙信号、钙流-线粒体 ROS 产生以及它们激活 NLRP3 炎性体的能力，研究了调节 SNP 核心疏水性性质对巨噬细胞的影响，从而提供了对炎性体激活的机制见解。我们建立了一个直接的相关性，即增加聚合物结构的侧链长度，从而增加 SNP 的核心疏水性，并增强 NLRP3 复合物的形成，这一点通过 ASC 斑点成像分析和升高的 1L-1β 表达来表明。此外，结果表明，根据 SNP 的疏水性侧链长度和重复单元，炎性体信号级联和动力学发生了变化。具体来说，具有最长烷基侧链的纳米颗粒通过线粒体损伤途径优先激活 NLRP3。在 C57BL/6 小鼠中对 SNPs 的评价证实了升高的促炎细胞因子，特别是具有最长 C-烷基侧链的 SNP。这证实了 SNP 更高的核心疏水性组成导致炎性体激活。总之，这项研究确立了 SNP 核心组成作为一种新型的与纳米颗粒相关的分子模式（NAMP），负责 NLRP3 炎性体的激活，为免疫治疗和疫苗应用中的纳米颗粒设计提供了复杂的细胞途径信息。
