Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400010, China.
Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing, 400715, China.
Biomaterials. 2023 Oct;301:122254. doi: 10.1016/j.biomaterials.2023.122254. Epub 2023 Jul 25.
Inflammatory bowel disease (IBD) has been closely associated with immune disorders and excessive M1 macrophage activation, which can be reversed by the M2-polarizing effect of interleukin-4 (IL-4). However, maintaining native IL-4 activity with its specific release in the inflammatory microenvironment and efficient biological performance remain a challenge. Inspired by the multilayered defense mechanism of the earth's atmosphere, we constructed a multilayered protective nanoarmor (NA) for IL-4 delivery (termed as IL-4@PEGRA NAs) into an intricate inflammatory microenvironment. The poly(ethylene glycol) (PEG)-ylated phenolic rosmarinic acid (RA)-grafted copolymer contains two protective layers-the intermediate polyphenol (RA molecules) and outermost shield (PEG) layers-to protect the biological activity of IL-4 and prolong its circulation in blood. Moreover, IL-4@PEGRA NAs scavenge reactive oxygen species with the specific release of IL-4 and maximize its biofunction at the site of inflammation, leading to M2 macrophage polarization and downregulation of inflammatory mediators. Simultaneously, gut microbiota dysbiosis can improve to amplify the M2-polarizing effect and inhibit the phosphatidylinositol 3 kinase/Akt signaling pathway, thereby attenuating inflammation and promoting colitis tissue repair. It provides a nature-inspired strategy for constructing an advanced multilayered NA delivery system with protective characteristics and potential for IBD management.
炎症性肠病 (IBD) 与免疫紊乱和过度的 M1 巨噬细胞激活密切相关，白细胞介素-4 (IL-4) 的 M2 极化作用可以逆转这种情况。然而，保持天然 IL-4 的活性，使其在炎症微环境中特异性释放，并具有高效的生物学性能，仍然是一个挑战。受地球大气层多层防御机制的启发，我们构建了一种用于白细胞介素-4 传递的多层保护纳米装甲（NA）（称为 IL-4@PEGRA NAs），以进入复杂的炎症微环境。聚乙二醇（PEG）化的迷迭香酸（RA）接枝共聚物包含两个保护层-中间多酚（RA 分子）和最外层屏蔽（PEG）层-以保护 IL-4 的生物活性并延长其在血液中的循环时间。此外，IL-4@PEGRA NAs 可清除活性氧，特异性释放 IL-4，并最大限度地发挥其在炎症部位的生物功能，导致 M2 巨噬细胞极化和炎症介质的下调。同时，肠道微生物失调可以改善 M2 极化作用，并抑制磷脂酰肌醇 3 激酶/Akt 信号通路，从而减轻炎症并促进结肠炎组织修复。它为构建具有保护特性和治疗 IBD 潜力的先进多层 NA 传递系统提供了一种受自然启发的策略。
