Silencing Gene-Engineered Injectable Hydrogel Microsphere for Regulation of Extracellular Matrix Metabolism Balance
Silencing Gene-Engineered Injectable Hydrogel Microsphere for Regulation of Extracellular Matrix Metabolism Balance
复制标题
沉默基因工程水凝胶微球调节细胞外基质代谢平衡的研究
DOI：
10.1002/smtd.202101201
复制
发表时间：
2022-01-06
期刊：
影响因子：
12.4
通讯作者：
Liu, Xiaodong
中科院分区：
文献类型：
--
作者：
Chang, Hongze;Cai, Feng;Liu, Xiaodong
细胞外基质（ECM）代谢平衡是维持组织结构和功能的必要条件。然而，ECM与常驻细胞和组织微环境之间复杂的串扰使得ECM在异常微环境下的代谢平衡难以长期维持。本研究通过酰胺键在甲基丙烯酸透明质酸（HAMA）微球上接枝含有circRNA沉默基因的1,2-二油基-3-三甲基丙烷/胆固醇/1,2-二油基- asn -甘油-3-磷酸乙醇胺（DOTAP/Chol/DOPE）阳离子脂质体，构建了可注射的circRNA沉默水凝胶微球（psh-circSTC2-lipo@MS），该微球可沉默髓核（NP）细胞中的病理基因，以调节营养限制微环境下ECM代谢平衡。从而抑制椎间盘退变。微流体制备的HAMA微球具有良好的可降解性、溶胀性和注射性。通过化学嫁接，脂质体可有效加载并释放27 d。在营养限制条件下共培养72 h， psh-circSTC2-lipo@MS显著促进NP细胞中ECM相关蛋白的合成，抑制ECM分解代谢相关蛋白酶的分泌。在IVD营养限制模型大鼠中，局部注射psh-circSTC2-lipo@MS可促进ECM合成，并在8周后恢复NP组织。综上所述，本研究证实psh-circSTC2-lipo@MS作为一种安全可控的靶向基因传递系统在异常微环境下调节ECM代谢平衡方面具有很大的潜力。
Extracellular matrix (ECM) metabolism balance is essential for maintaining tissue structure and function. However, the complex crosstalk between the ECM, resident cellular, and tissue microenvironment makes long-term maintenance of ECM metabolism balance in an abnormal microenvironment difficult to achieve. Herein, an injectable circRNA silencing-hydrogel microsphere (psh-circSTC2-lipo@MS) is constructed by grafting circSTC2 silencing genes-loaded 1,2-dioleoyl-3-trimethylammonium-propane/cholesterol/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOTAP/Chol/DOPE) cationic liposomes on methacrylated hyaluronic acid (HAMA) microspheres via amide bonds, which could silence pathological genes in nucleus pulposus (NP) cells to regulate ECM metabolism balance in the nutrient-restricted microenvironment, thereby inhibiting intervertebral disc (IVD) degeneration. HAMA microspheres prepared by microfluidics displayed good degradability, swellability, and injectability. And lipoplexes can be efficiently loaded and released for 27 d through chemical grafting. Cocultured under nutrient-restricted conditions for 72 h, psh-circSTC2-lipo@MS significantly promotes the synthesis of ECM-related proteins and inhibits the secretion of ECM catabolism-related proteases in NP cells. In the rat IVD nutrient-restricted model, local injection of psh-circSTC2-lipo@MS promotes ECM synthesis and restored NP tissue after 8 weeks. In summary, this study confirms that psh-circSTC2-lipo@MS as a safe and controllable targeted gene delivery system has great potential in regulating the ECM metabolism balance under an abnormal microenvironment.