基于贝加肽的可吸入生物活性脂质纳米药物通过协调巨噬细胞极化实现急性肺损伤靶向治疗

IF 18 1区 医学 Q1 ENGINEERING, BIOMEDICAL
Ran Liao , Zhi-Chao Sun , Liying Wang , Caihong Xian , Ran Lin , Guifeng Zhuo , Haiyan Wang , Yifei Fang , Yuntao Liu , Rongyuan Yang , Jun Wu , Zhongde Zhang
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引用次数: 0

摘要

急性肺损伤(ALI)或更严重的急性呼吸窘迫综合征是一种危及生命的疾病,与 M1/M2 巨噬细胞极化失衡密切相关。然而,由于副作用、给药途径受限或靶向性差等原因,目前针对 ALI 的治疗策略存在争议。中草药的发展发现了许多可能有益于 ALI 治疗的抗炎化合物。其中一种化合物是从榕树中分离出来的香豆素--bergapten。不过,它一直被用作抗癌药物,对 ALI 的作用仍有待探索。bergapten 的溶解性和生物分布较差,严重限制了它的应用。在这篇及时的报告中,我们通过整合bergapten和DPPC脂质体,开发出了一种具有生物活性的肺靶向脂质纳米药物,命名为Ber-lipo。一系列全面的体外实验证实了 Ber-lipo 的抗炎作用及其在维持巨噬细胞极化平衡和上皮-内皮完整性方面的保护作用。在脂多糖(LPS)诱导的 ALI 小鼠模型中,Ber-lipo 可以靶向炎症肺,显著改善肺水肿、组织损伤和肺功能,减轻体重下降、肺通透性和促炎状态,尤其是维持 M1/M2 巨噬细胞极化的平衡。此外,RNA 测序分析表明 Ber-lipo 可有效治疗肺炎等肺部炎症性疾病,抑制促炎信号,改变肺组织中 M1/M2 巨噬细胞相关基因的转录组。分子对接和 Western 印迹分析验证了 Ber-lipo 可抑制导致 ALI 进展的 TLR4/MyD88/NF-κB 信号轴的激活。总之,本研究首次证明了新型可吸入纳米药物(Ber-lipo)可以靶向发炎的肺部,并通过灭活TLR4/MyD88/NF-κB通路将巨噬细胞极化重编程为抗炎状态来改善ALI,从而为临床上加强ALI治疗提供了一种前景广阔的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inhalable and bioactive lipid-nanomedicine based on bergapten for targeted acute lung injury therapy via orchestrating macrophage polarization

Inhalable and bioactive lipid-nanomedicine based on bergapten for targeted acute lung injury therapy via orchestrating macrophage polarization
Acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome, is a life-threatening disease closely associated with an imbalance of M1/M2 macrophage polarization. However, current therapeutic strategies for ALI are controversial due to their side effects, restricted administration routes, or poor targeted delivery. The development of herbal medicine has uncovered numerous anti-inflammatory compounds potentially beneficial for ALI therapy. One such compound is the bergapten, a coumarin, which has been isolated from Ficus simplicissima Lour. However, it's been used as an anti-cancer drug and it's effects on ALI remain unexplored. The poor solubility and biodistribution of bergapten heavily limit its application. In this timely report, we developed a bioactive and lung-targeting lipid-nanomedicine by integrating bergapten and DPPC liposome, named as Ber-lipo. A comprehensive series of in vitro experiments confirmed the anti-inflammatory effects of Ber-lipo and its protective roles in maintaining the homeostasis of macrophage polarization and epithelial–endothelial integrity. In a lipopolysaccharide (LPS)-induced ALI mouse model, Ber-lipo can target inflamed lungs and significantly improve lung edema, tissue injury, and pulmonary function, relieve body weight loss, pulmonary permeability, and proinflammatory status, and especially maintain a balance of M1/M2 macrophage polarization. Furthermore, RNA sequencing analysis showed Ber-lipo's potential in effectively treating inflammatory lung diseases such as pneumonia, inhibiting proinflammatory signals, and altering the transcriptome of M1/M2 macrophages-associated genes in lung tissues. Molecular docking and Western blot analyses validated that Ber-lipo suppressed the activation of the TLR4/MyD88/NF-κB signaling axis responsible for ALI progression. In conclusion, this study demonstrates for the first time that new inhalable nanomedicine (Ber-lipo) can target inflamed lungs and ameliorates ALI by reprogramming macrophage polarization to an anti-inflammatory state via inactivating the TLR4/MyD88/NF-κB pathway, hence providing a promising strategy for enhanced ALI therapy in the clinic.
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来源期刊
Bioactive Materials
Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology
CiteScore
28.00
自引率
6.30%
发文量
436
审稿时长
20 days
期刊介绍: Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.
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