Programmed Release METTL3-14 Inhibitor Microneedle Protects Myocardial Function by Reducing Drp1 m6A Modification-Mediated Mitochondrial Fission

作者全名："Huang, Boyue; Xie, Liu; Ke, Ming; Fan, Yonghong; Tan, Ju; Ran, Jianhua; Zhu, Chuhong"

作者地址："[Huang, Boyue; Ran, Jianhua] Chongqing Med Univ, Basic Med Coll, Dept Anat, Chongqing 400016, Peoples R China; [Huang, Boyue; Ran, Jianhua] Chongqing Med Univ, Basic Med Coll, Lab Neurosci & Tissue Engn, Chongqing 400016, Peoples R China; [Xie, Liu; Ke, Ming; Fan, Yonghong; Tan, Ju; Zhu, Chuhong] Third Mil Med Univ, Engn Res Ctr Organ Intelligent Biol Mfg Chongqing, Dept Anat, Key Lab Biomech & Tissue Engn Chongqing, Chongqing 400038, Peoples R China; [Xie, Liu] Hunan Med Coll, Dept Pathol & Pathophysiol, Huaihua 418000, Peoples R China; [Zhu, Chuhong] Minist Educ, Engn Res Ctr Tissue & Organ Regenerat & Mfg, Chongqing 400038, Peoples R China; [Zhu, Chuhong] State Key Lab Trauma, Burn & Combined Injury, Chongqing 400038, Peoples R China"

通信作者："Ran, JH (通讯作者)，Chongqing Med Univ, Basic Med Coll, Dept Anat, Chongqing 400016, Peoples R China.; Ran, JH (通讯作者)，Chongqing Med Univ, Basic Med Coll, Lab Neurosci & Tissue Engn, Chongqing 400016, Peoples R China.; Zhu, CH (通讯作者)，Third Mil Med Univ, Engn Res Ctr Organ Intelligent Biol Mfg Chongqing, Dept Anat, Key Lab Biomech & Tissue Engn Chongqing, Chongqing 400038, Peoples R China.; Zhu, CH (通讯作者)，Minist Educ, Engn Res Ctr Tissue & Organ Regenerat & Mfg, Chongqing 400038, Peoples R China.; Zhu, CH (通讯作者)，State Key Lab Trauma, Burn & Combined Injury, Chongqing 400038, Peoples R China."

来源：ACS APPLIED MATERIALS & INTERFACES

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:001076953400001

JCR分区：Q1

影响因子：8.3

年份：2023

卷号：15

期号：40

开始页：46583

结束页：46597

文献类型：Article

关键词：microneedle; mitochondrial fission; Drp1; myocardial infarction; METTL3

摘要："M6A modification is an RNA-important processing event mediated by methyltransferases METTL3 and METTL14 and the demethylases. M6A dynamic changes after myocardial infarction (MI), involved in the massive loss of cardiomyocytes due to hypoxia, as well as the recruitment and activation of myofibroblasts. Balanced mitochondrial fusion and fission are essential to maintain intracardiac homeostasis and reduce poststress myocardial remodeling. Double-layer programmed drug release microneedle (DPDMN) breaks the limitations of existing therapeutic interventions in one period or one type of cells, and multitargeted cellular combination has more potential in MI therapy. By employing hypoxia-ischemic and TGF-beta 1-induced fibrosis cell models, we found that METTL3-14 inhibition effectively decreased cardiomyocyte death through the reduction of mitochondrial fragmentation and inhibiting myofibrillar transformation. DPDMN treatment of MI in rat models showed improved cardiac function and decreased infarct size and fibrosis level, demonstrating its superior effectiveness. The DPDMN delivers METTL3 inhibitor swiftly in the early phase to rescue dying cardiomyocytes and slowly in the late phase to achieve long-term suppression of fibroblast over proliferation, collagen synthesis, and deposition. RIP assay and mechanistic investigation confirmed that METTL3 inhibition reduced the translation efficiency of Drp1 mRNA by 5 ' UTR m6A modification, thus decreasing the Drp1 protein level and mitochondrial fragment after hypoxic-ischemic injury. This project investigated the efficacy of DPDMNs-loaded METTL3 inhibitor in MI treatment and the downstream signaling pathway proteins, providing an experimental foundation for the translation of the utility, safety, and versatility of microneedle drug delivery for MI into clinical applications."

基金机构："Key Projects of the National Natural Science Foundation of China [81830055, 82230073]; Outstanding Scientist Project of Chongqing [cstc2022ycjh-bgzxm0186]; National Natural Science Foundation of China [81770738]; Natural Science Foundation of Chongqing [CSTB2022NSCQ-BHX0714, CSTB2023NSCQ-MSX0510]; Chongqing Postdoctoral Research Project Special Support [2022CQBSHTB2058]; Chongqing Key Laboratory for the Development and Utilization of Precious Medicinal Materials in the Three Gorges Reservoir Area of Chongqing Municipality [KFKT2022010]; Excellent Youth Program of Hunan Provincial Department of Education [21B0908]"

基金资助正文："This work was supported by Key Projects of the National Natural Science Foundation of China (81830055, 82230073), Outstanding Scientist Project of Chongqing (cstc2022ycjh-bgzxm0186), grants from the National Natural Science Foundation of China (81770738), the Natural Science Foundation of Chongqing (CSTB2022NSCQ-BHX0714, CSTB2023NSCQ-MSX0510), Chongqing Postdoctoral Research Project Special Support (2022CQBSHTB2058), Chongqing Key Laboratory for the Development and Utilization of Precious Medicinal Materials in the Three Gorges Reservoir Area of Chongqing Municipality (KFKT2022010), and Excellent Youth Program of Hunan Provincial Department of Education (21B0908)."