Sheng Ruxiang, Wang Wei, Zeng Weian, Li Bin, Yu Haoyuan, Li Xuan, Liang Yanqiu, Wang Ying, Liao Yuhui, Liu Dezhao
Department of Anesthesiology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, People's Republic of China.
Molecular Diagnosis and Treatment Center for Infectious Diseases Dermatology Hospital of Southern Medical University, Guangzhou, 510091, People's Republic of China.
Int J Nanomedicine. 2025 Mar 18;20:3541-3557. doi: 10.2147/IJN.S507546. eCollection 2025.
Intestinal ischemia-reperfusion (I/R) injury is a common and severe clinical issue. With high morbidity and mortality, it burdens patients and the healthcare system. Despite the efforts in medical research, current treatment options are unsatisfactory, urging novel therapeutic strategies. Oxidative stress and dysregulated autophagy play pivotal roles in the pathogenesis of I/R injury, damaging intestinal tissues and disrupting normal functions. The aim of this study is to fabricate macrophage membrane-coated manganese dioxide nanospheres loaded with rapamycin [Ma@(MnO₂+RAPA)] for alleviating intestinal I/R injury.
We engineered honeycomb MnO nanospheres coated with a macrophage membrane to act as a drug delivery system, encapsulating RAPA. In vitro OGD/R model in IEC-6 cells and in vivo mouse I/R injury models were used. Targeting ability was evaluated through in-vivo imaging system. Effects on cell viability, reactive oxygen species (ROS) levels, oxygen generation, inflammatory factors, apoptosis, autophagy, and biocompatibility were detected by methods such as MTT assay, fluorescence microscopy, ELISA kit, TUNEL assay, Western blotting and histological analysis.
In this study, Ma@(MnO₂+RAPA) efficiently deliver RAPA to damaged tissues and exhibited good ROS-responsive release. Our data showed that Ma@(MnO₂+RAPA) reduced ROS, increased O₂, inhibited inflammation, and promoted autophagy while reducing apoptosis in IEC-6 cells. In a mouse I/R model, Ma@(MnO₂+RAPA) significantly reduced Chiu's score, improved tight conjunction proteins, decreased apoptosis, reduced levels of inflammatory cytokines and oxidative stress. RAPA released from the Ma@(MnO₂+RAPA), enhanced the expression of autophagy-regulated proteins p62, Beclin-1, and LC3II. The biocompatibility and safety of Ma@(MnO₂+RAPA) were confirmed through histological analysis and biochemical detection in mice.
Our results demonstrated that Ma@(MnO₂+RAPA) alleviated intestinal I/R injury by reducing oxidative stress, promoting autophagy, and inhibiting inflammation. This study offers a potential therapeutic strategy for the treatment of intestinal ischemia-reperfusion injury.
肠道缺血再灌注（I/R）损伤是一个常见且严重的临床问题。其发病率和死亡率高，给患者和医疗系统带来负担。尽管医学研究不断努力，但目前的治疗选择仍不尽人意，迫切需要新的治疗策略。氧化应激和自噬失调在I/R损伤的发病机制中起关键作用，会损害肠道组织并扰乱正常功能。本研究的目的是制备负载雷帕霉素的巨噬细胞膜包被二氧化锰纳米球[Ma@(MnO₂+RAPA)]以减轻肠道I/R损伤。
我们构建了用巨噬细胞膜包被的蜂窝状MnO纳米球作为药物递送系统，包裹雷帕霉素。使用IEC-6细胞的体外氧糖剥夺/再灌注（OGD/R）模型和体内小鼠I/R损伤模型。通过体内成像系统评估靶向能力。通过MTT法、荧光显微镜、ELISA试剂盒、TUNEL法、蛋白质印迹法和组织学分析等方法检测对细胞活力、活性氧（ROS）水平、氧气生成、炎症因子、凋亡、自噬和生物相容性的影响。
在本研究中，Ma@(MnO₂+RAPA)能有效地将雷帕霉素递送至受损组织，并表现出良好的ROS响应释放。我们的数据表明，Ma@(MnO₂+RAPA)可降低IEC-6细胞中的ROS水平、增加氧气生成、抑制炎症并促进自噬，同时减少凋亡。在小鼠I/R模型中，Ma@(MnO₂+RAPA)显著降低了Chiu评分，改善了紧密连接蛋白，减少了凋亡，降低了炎症细胞因子水平和氧化应激。从Ma@(MnO₂+RAPA)释放的雷帕霉素增强了自噬调节蛋白p62、Beclin-1和LC3II的表达。通过小鼠的组织学分析和生化检测证实了Ma@(MnO₂+RAPA)的生物相容性和安全性。
我们的结果表明，Ma@(MnO₂+RAPA)通过减轻氧化应激、促进自噬和抑制炎症来减轻肠道I/R损伤。本研究为肠道缺血再灌注损伤的治疗提供了一种潜在的治疗策略。
