Jiang Jing-Si, Zang Jie, Ru Yi, Luo Ying, Song Jian-Kun, Luo Yue, Fei Xiao-Ya, Zhang Zhan, Zhang Ying, Yang Dan, Zhou Mi, Chen Qi-Long, Bai Yun, Li Yong-Yong, Kuai Le, Li Bin
Shanghai Skin Disease Hospital of Tongji University, Shanghai, 200443, China.
The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai, 200092, China.
Biomaterials. 2022 Sep;288:121698. doi: 10.1016/j.biomaterials.2022.121698. Epub 2022 Aug 15.
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 blocked in 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 both in vitro and in 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.
糖尿病溃疡（DUs）是糖尿病的一种严重并发症，临床上由于有效干预措施有限而难以治疗。基于临床样本和生物信息学分析，我们发现DU患者体内CCN1水平较低。考虑到CCN1对角质形成细胞的促增殖作用，我们提出补充CCN1在DU微环境中的治疗作用。为应对在富含蛋白酶的糖尿病愈合环境中CCN1快速降解的挑战，我们制备了CCN1纳米制剂（CCN1-NP），它可保护CCN1不被降解，并将CCN1的细胞内递送效率显著提高到6.2倍。结果表明，在体外一旦CCN1的细胞外信号被阻断，细胞内的CCN1就会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机制，即进入细胞的CCN1与真核翻译起始因子3亚基A（EIF3A）相互作用，下调自噬相关蛋白7（ATG7）。此外，CCN1-NP的局部应用在体外和体内对糖尿病延迟伤口愈合均有显著疗效。我们的结果阐明了由纳米制剂触发的细胞内EIF3A/CCN1/ATG7轴的新机制以及CCN1-NP在治疗DU方面的潜力。
