Strathclyde Institute of Pharmacy and Biomedical Sciences , University of Strathclyde , 161 Cathedral Street , Glasgow G4 0RE , U.K.
CICECO - Aveiro Institute of Materials, Department of Chemistry , University of Aveiro , 3810-193 Aveiro , Portugal.
ACS Appl Mater Interfaces. 2019 Apr 24;11(16):14515-14525. doi: 10.1021/acsami.8b18716. Epub 2019 Apr 12.
Silk fibroin nanoparticles are emerging as promising nanomedicines, but their full therapeutic potential is yet to be realized. These nanoparticles can be readily PEGylated to improve colloidal stability and to tune degradation and drug release profiles; however, the relationship between silk fibroin nanoparticle PEGylation and macrophage activation still requires elucidation. Here, we used in vitro assays and nuclear magnetic resonance based metabolomics to examine the inflammatory phenotype and metabolic profiles of macrophages following their exposure to unmodified or PEGylated silk fibroin nanoparticles. The macrophages internalized both types of nanoparticles, but they showed different phenotypic and metabolic responses to each nanoparticle type. Unmodified silk fibroin nanoparticles induced the upregulation of several processes, including production of proinflammatory mediators (e.g., cytokines), release of nitric oxide, and promotion of antioxidant activity. These responses were accompanied by changes in the macrophage metabolomic profiles that were consistent with a proinflammatory state and that indicated an increase in glycolysis and reprogramming of the tricarboxylic acid cycle and the creatine kinase/phosphocreatine pathway. By contrast, PEGylated silk fibroin nanoparticles induced milder changes to both inflammatory and metabolic profiles, suggesting that immunomodulation of macrophages with silk fibroin nanoparticles is PEGylation-dependent. Overall, PEGylation of silk fibroin nanoparticles reduced the inflammatory and metabolic responses initiated by macrophages, and this observation could be used to guide the therapeutic applications of these nanoparticles.
丝素纳米颗粒作为有前途的纳米药物正在兴起，但它们的全部治疗潜力尚未得到实现。这些纳米颗粒可以很容易地进行聚乙二醇化以提高胶体稳定性，并调整降解和药物释放特性；然而，丝素纳米颗粒聚乙二醇化和巨噬细胞激活之间的关系仍需要阐明。在这里，我们使用体外测定和基于核磁共振的代谢组学来研究未修饰或聚乙二醇化的丝素纳米颗粒暴露后巨噬细胞的炎症表型和代谢谱。巨噬细胞内化了这两种类型的纳米颗粒，但它们对每种纳米颗粒类型表现出不同的表型和代谢反应。未修饰的丝素纳米颗粒诱导了几种过程的上调，包括促炎介质（例如细胞因子）的产生、一氧化氮的释放和抗氧化活性的促进。这些反应伴随着巨噬细胞代谢组学图谱的变化，与炎症状态一致，并表明糖酵解增加以及三羧酸循环和肌酸激酶/磷酸肌酸途径的重新编程。相比之下，聚乙二醇化的丝素纳米颗粒对炎症和代谢谱的变化较小，表明丝素纳米颗粒对巨噬细胞的免疫调节依赖于聚乙二醇化。总的来说，丝素纳米颗粒的聚乙二醇化降低了巨噬细胞引发的炎症和代谢反应，这一观察结果可用于指导这些纳米颗粒的治疗应用。
