Targeting m6A demethylase FTO to heal diabetic wounds with ROS-scavenging nanocolloidal hydrogels

IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL
Xinyao Zheng , Shaohui Deng , Yuan Li , Zhipeng Luo , Ziqi Gan , Zhaoping Zheng , Rui Xu , Shan Xiao , Yuxiong Cai , Jianfu Meng , Li Li , Changxing Li , Xiaowen Xue , Wei Dai , Si Qin , Mengying Wang , Kang Zeng , Zecong Xiao , Laixin Xia
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Abstract

Chronic diabetic wounds are a prevalent and severe complication of diabetes, contributing to higher rates of limb amputations and mortality. N6-methyladenosine (m6A) is a common RNA modification that has been shown to regulate tissue repair and regeneration. However, whether targeting m6A could effectively improve chronic diabetic wound healing remains largely unknown. Here, we found a significant reduction in mRNA m6A methylation levels within human diabetic foot ulcers, and the expression level of fat mass and obesity-associated protein (FTO) was significantly increased. We identified that m6A modifies the RNA of matrix Metalloproteinase 9 (MMP9), a key factor in diabetic wound healing, to regulate its expression. Importantly, we developed a ROS-scavenging nanocolloidal hydrogel loaded with an FTO inhibitor to increase the m6A level of MMP9 RNA in wounds. The hydrogel can effectively accelerate wound healing and skin appendage regeneration in streptozotocin-induced type I diabetic rats at day 14 (approximately 98 % compared to 76.98 % in the control group) and type II diabetic db/db mice at day 20 (approximately 93 % compared to 60 % in the control group). Overall, our findings indicate that targeting m6A with ROS-scavenging hydrogel loaded with FTO inhibitor may be an effective therapeutic strategy for diabetic wound healing.
靶向m6A去甲基化酶FTO的ros清除纳米胶体水凝胶治疗糖尿病伤口。
慢性糖尿病伤口是糖尿病的一种普遍和严重的并发症,导致较高的截肢率和死亡率。n6 -甲基腺苷(m6A)是一种常见的RNA修饰,已被证明可以调节组织修复和再生。然而,靶向m6A是否能有效改善慢性糖尿病伤口愈合仍不得而知。在这里,我们发现人类糖尿病足溃疡中mRNA m6A甲基化水平显著降低,脂肪量和肥胖相关蛋白(FTO)的表达水平显著升高。我们发现m6A修饰基质金属蛋白酶9 (MMP9)的RNA,以调节其表达,MMP9是糖尿病伤口愈合的关键因素。重要的是,我们开发了一种装载FTO抑制剂的ros清除纳米胶体水凝胶,以增加伤口中MMP9 RNA的m6A水平。在链脲佐菌素诱导的第14天I型糖尿病大鼠(约98%,对照组为76.98%)和第20天II型糖尿病db/db小鼠(约93%,对照组为60%)中,水凝胶可以有效地加速伤口愈合和皮肤附属物再生。总之,我们的研究结果表明,装载FTO抑制剂的ros清除水凝胶靶向m6A可能是糖尿病伤口愈合的有效治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biomaterials
Biomaterials 工程技术-材料科学:生物材料
CiteScore
26.00
自引率
2.90%
发文量
565
审稿时长
46 days
期刊介绍: Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.
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