Ren Jianheng, Hua Yuanyi, Liao Zhumei, Wen Xin, Wang Qin
Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China.
Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China.
Acta Biomater. 2025 Oct 17. doi: 10.1016/j.actbio.2025.10.029.
Researchers have made significant efforts to develop mitochondria or endoplasmic reticulum (ER)-targeting strategies to regulate cellular signaling cascades in inflammatory diseases. Although ER and mitochondria function relatively independently, these organelles can form extensive physical interactions, known as mitochondria-associated ER membranes (MAMs). Emerging evidence suggests that the development of inflammatory diseases depends largely on the pathological crosstalk between mitochondria and ER through MAMs, whereby ER stress and mitochondrial dysfunction collectively activate inflammatory signaling. Due to the presence of MAMs, single-organelle (ER or mitochondria)-specific therapies may not adequately suppress inflammatory signaling activation, highlighting the need for two-pronged strategies to thoroughly interfere with the pathological crosstalk between ER and mitochondria. This review highlights how the interaction between mitochondria and ER contributes to the progression of inflammatory diseases, and systematically summarizes the current advances in delivery strategies for ER and mitochondria targeting. Furthermore, we emphasize the therapeutic potential of simultaneously regulating mitochondrial and ER function to achieve precise control of inflammatory disorders. Our review aims to establish a framework for two-pronged targeting strategies that can restore ER and mitochondrial homeostasis, thereby facilitating the treatment of inflammatory diseases. STATEMENT OF SIGNIFICANCE: Due to the extensively formed mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) under inflammatory conditions, previous studies focusing on modulating the dysfunction of either mitochondria or ER have demonstrated limited efficacy in inflammatory disorders. MAM-mediated pathological inter-organelles crosstalk can drive the vicious cycle between mitochondria dysfunction and ER stress in inflammatory diseases, underscoring the need for two-pronged approaches that precisely disrupting mitochondria-ER communication. This review highlighted the key role of MAMs in inflammation and summarized recent advances in ER/mitochondria targeted delivery strategies. Furthermore, we underscored the potential therapeutic targets within MAMs for inflammatory intervention, and discussed therapeutic potential of two-pronged approaches in restoring organelle homeostasis and mitigating inflammatory diseases.
研究人员已付出巨大努力来开发线粒体或内质网（ER）靶向策略，以调节炎症性疾病中的细胞信号级联反应。尽管内质网和线粒体功能相对独立，但这些细胞器可形成广泛的物理相互作用，即线粒体相关内质网膜（MAMs）。新出现的证据表明，炎症性疾病的发展在很大程度上取决于线粒体和内质网通过MAMs发生的病理性串扰，由此内质网应激和线粒体功能障碍共同激活炎症信号。由于存在MAMs，单一细胞器（内质网或线粒体）特异性疗法可能无法充分抑制炎症信号激活，这凸显了采取双管齐下策略以彻底干扰内质网和线粒体之间病理性串扰的必要性。本综述强调了线粒体与内质网之间的相互作用如何促进炎症性疾病的进展，并系统总结了内质网和线粒体靶向递送策略的当前进展。此外，我们强调了同时调节线粒体和内质网功能以实现对炎症性疾病精确控制的治疗潜力。我们的综述旨在建立一个双管齐下靶向策略的框架，该框架可恢复内质网和线粒体的稳态，从而促进炎症性疾病的治疗。重要性声明：由于在炎症条件下广泛形成了线粒体相关内质网膜（MAMs），先前专注于调节线粒体或内质网功能障碍的研究在炎症性疾病中显示出有限的疗效。MAM介导的病理性细胞器间串扰可驱动炎症性疾病中线粒体功能障碍和内质网应激之间的恶性循环，强调了需要采取双管齐下的方法来精确破坏线粒体 - 内质网通讯。本综述强调了MAMs在炎症中的关键作用，并总结了内质网/线粒体靶向递送策略的最新进展。此外，我们强调了MAMs内用于炎症干预的潜在治疗靶点，并讨论了双管齐下方法在恢复细胞器稳态和减轻炎症性疾病方面的治疗潜力。
