Patient-driven discovery of CCN1 to rescue cutaneous wound healing in diabetes via the intracellular EIF3A/CCN1/ATG7 signaling by nanoparticle-enabled delivery
Patient-driven discovery of CCN1 to rescue cutaneous wound healing in diabetes via the intracellular EIF3A/CCN1/ATG7 signaling by nanoparticle-enabled delivery
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由患者驱动的 CCN1 发现，通过纳米颗粒递送的细胞内 EIF3A/CCN1/ATG7 信号传导来挽救糖尿病皮肤伤口愈合
DOI：
10.1016/j.biomaterials.2022.121698
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发表时间：
2022-09-01
期刊：
影响因子：
14
通讯作者：
Li，Bin
中科院分区：
文献类型：
--
作者：
Jiang，Jing-Si;Zang，Jie;Li，Bin
糖尿病溃疡是糖尿病的一种严重并发症，临床上治疗效果不佳。基于临床样本和生物信息学分析，我们发现DU个体中CCN 1水平较低。考虑到角质形成细胞的加速增殖作用，我们提出了在DU微环境中补充CCN 1的治疗作用。为了解决CCN 1在富含蛋白酶的糖尿病愈合条件下快速降解的挑战，我们制备了CCN 1的纳米制剂（CCN 1-NP），其保护CCN 1免受降解，并将CCN 1细胞内递送效率显著提高至6.2倍。结果表明，当体外阻断CCN 1的细胞外信号后，细胞内CCN 1表现出更强的抗炎和增殖/迁移活性。该纳米制剂揭示了一种新的机制，即CCN 1被递送到细胞中，与真核翻译起始因子3亚基A（EIF 3A）相互作用，以下调自噬相关7（ATG 7）。此外，局部应用CCN 1-NP在体外和体内均对糖尿病伤口延迟愈合具有显著疗效。我们的研究结果说明了纳米制剂触发的细胞内EIF 3A/CCN 1/ATG 7轴的新机制以及CCN 1-NP用于DU管理的治疗潜力。
Diabetic ulcers (DUs), a devastating complication of diabetes, are intractable for limited effective interventions in clinic. Based on the clinical samples and bioinformatic analysis, we found lower level of CCN1 in DU individuals. Considering the accelerated proliferation effect in keratinocytes, we propose the therapeutic role of CCN1 supplementation in DU microenvironment. To address the challenge of rapid degradation of CCN1 in protease-rich diabetic healing condition, we fabricated a nanoformulation of CCN1 (CCN1-NP), which protected CCN1 from degradation and significantly raised CCN1 intracellular delivery efficiency to 6.2-fold. The results showed that the intracellular CCN1 exhibited a greater anti-inflammatory and proliferative/migratory activities once the extracellular signal of CCN1 was blockedin vitro. The nanoformulation unveils a new mechanism that CCN1 delivered into cells interacted with Eukaryotic translation initiation factor 3 subunit A (EIF3A) to downregulate autophagy-related 7 (ATG7). Furthermore, topical application of CCN1-NP had profound curative effects on delayed wound healing in diabetes bothin vitroandin vivo. Our results illustrate a novel mechanism of intracellular EIF3A/CCN1/ATG7 axis triggered by nanoformulation and the therapeutic potential of CCN1-NP for DU management.