结合中性粒细胞包被的二维金属卟啉框架纳米片和exendin-4的仿生多模态纳米平台治疗肥胖相关性骨质疏松症

IF 8.7 1区医学 Q1 ENGINEERING, BIOMEDICAL

Materials Today Bio Pub Date : 2025-06-21 DOI:10.1016/j.mtbio.2025.102009

Qifan Yang , Jing Liu , Yanwei Liu , Shun Liu , Xiaokang Wei , Yilin Yang , Weijie Zhang , Shuqi Zhang , Maosheng Zhang , Bin Liu , Xinyu Wang , Dong Zhu

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引用次数: 0

摘要

背景：肥胖引起的骨质疏松症是肥胖人群中常见的并发症。传统的抗骨质疏松药物往往缺乏治疗特异性，并可能加剧脂质代谢紊乱。因此，确定适当的药物干预措施，阐明其潜在的生物学机制，以及开发具有增强生物相容性和靶向递送的纳米药物递送系统仍然是重大挑战。方法本研究揭示肥胖性骨质疏松的发病机制主要是由过度的线粒体自噬驱动的。值得注意的是，Exendin-4 （Ex-4）已被证明可以改善线粒体自噬并减轻肥胖引起的骨质疏松症。DSPE-PEG-ALN (DPA)@中性粒细胞膜（NM）@Cu-TCPP(Zn)/Ex-4 （CTZE）纳米复合材料具有高生物相容性和活性氧（ROS）响应性，可有效靶向骨组织，降低ROS水平，调节Cu2+、Zn2+、Ex-4和Alendronate （ALN）的释放。该复合物通过tet甲基胞嘧啶双加氧酶2 (TET2)/ pten诱导的推定激酶蛋白1 (PINK1)/Parkin （E3泛素蛋白连接酶Parkin）途径干扰b细胞淋巴瘤-2 (BCL2)- Beclin-1 （BECN1）结合，从而促进成骨细胞分化和矿化。在肥胖性骨质疏松小鼠模型中验证了该纳米递送平台的安全性和有效性。综上所述，我们的研究表明过度的线粒体自噬在肥胖性骨质疏松症中起着至关重要的作用。此外，DPA@NM@CTZE在精确治疗肥胖性骨质疏松症、减轻Ex-4副作用和改善骨微环境方面显示出显著的潜力。

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A biomimetic multimodal nanoplatform combining neutrophil-coated two-dimensional metalloporphyrinic framework nanosheet and exendin-4 to treat obesity-related osteoporosis

Background

Obesity-induced osteoporosis is a prevalent complication among obese individuals. Conventional anti-osteoporosis medications often lack therapeutic specificity and may exacerbate lipid metabolism disorders. Consequently, identifying suitable pharmacological interventions for obesity-induced osteoporosis, elucidating its underlying biological mechanisms, and developing nanodrug delivery systems with enhanced biocompatibility and targeted delivery remain significant challenges.

Methods

This study reveals that the pathogenesis of obesity-induced osteoporosis is primarily driven by excessive mitophagy. Notably, Exendin-4 (Ex-4) has been shown to ameliorate mitophagy and mitigate obesity-induced osteoporosis. The nanocomposite DSPE-PEG-ALN (DPA)@Neutrophil membrane (NM)@Cu-TCPP(Zn)/Ex-4 (CTZE), characterized by high biocompatibility and reactive oxygen species (ROS) responsiveness, effectively targets bone tissue, reduces ROS levels, and regulates the release of Cu²⁺, Zn²⁺, Ex-4, and Alendronate (ALN). This composite interferes with B-cell lymphoma-2 (BCL2)- Beclin-1 (BECN1) binding via the tet methylcytosine dioxygenase 2 (TET2)/PTEN-induced putative kinase protein 1 (PINK1)/Parkin (E3 ubiquitin-protein ligase parkin) pathway, thereby promoting osteoblast differentiation and mineralization. The safety and efficacy of this nano-delivery platform were validated in a mouse model of obesity-induced osteoporosis.

Conclusions

In summary, our study illustrates that excessive mitophagy plays a crucial role in obesity-induced osteoporosis. Furthermore, DPA@NM@CTZE exhibits significant potential for the precise treatment of obesity-induced osteoporosis, mitigating the side effects of Ex-4, and enhancing the bone microenvironment.

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来源期刊

Materials Today Bio Multiple-

CiteScore

8.30

自引率

4.90%

发文量

303

审稿时长

30 days

期刊介绍： Materials Today Bio is a multidisciplinary journal that specializes in the intersection between biology and materials science, chemistry, physics, engineering, and medicine. It covers various aspects such as the design and assembly of new structures, their interaction with biological systems, functionalization, bioimaging, therapies, and diagnostics in healthcare. The journal aims to showcase the most significant advancements and discoveries in this field. As part of the Materials Today family, Materials Today Bio provides rigorous peer review, quick decision-making, and high visibility for authors. It is indexed in Scopus, PubMed Central, Emerging Sources, Citation Index (ESCI), and Directory of Open Access Journals (DOAJ).