Injectable "nano-micron" combined gene-hydrogel microspheres for local treatment of osteoarthritis
Injectable "nano-micron" combined gene-hydrogel microspheres for local treatment of osteoarthritis
复制标题
可注射-纳米-微米-组合基因-水凝胶微球用于骨关节炎的局部治疗
DOI：
10.1038/s41427-021-00351-7
复制
发表时间：
2022-01-07
影响因子：
9.7
通讯作者：
Cui, Wenguo
中科院分区：
文献类型：
--
作者：
Li, Bin;Wang, Fei;Cui, Wenguo
持续可控的局部基因治疗是通过将治疗性microRNA（miRNAs）递送至靶细胞来治疗骨关节炎（OA）的潜在方法。然而，直接注射用于局部基因治疗的粗miRNAs由于其不充分的转染效率、容易失活和短半衰期而受到限制。在此，使用多功能基因载体精氨酸、组氨酸和苯丙氨酸修饰的第5代聚酰胺胺（命名为G5-AHP）通过与microRNA-140（miR-140）形成复合物来形成G5-AHP/miR-140纳米颗粒。然后将纳米粒包埋在水凝胶微球中，构建“纳-微米”复合基因水凝胶，以减轻关节软骨的降解。单分散明胶甲基丙烯酰水凝胶MS在紫外光下使用一步创新的微流控技术生产。在用于局部基因递送的可持续和基质金属蛋白酶（MMPs）响应性降解方法中，雌二醇分散的MS显示出更好的可注射性。从MS释放的G5-AHP/miR-140纳米颗粒表现出高基因转染效率和长期生物活性，促进内吞作用，从而通过促进软骨细胞中II型胶原的表达并抑制具有血小板反应蛋白基序-5和MMP 13的去整合素和金属蛋白酶的表达来维持软骨基质的代谢平衡。在将“纳米-微米”组合的基因水凝胶注射到OA模型的关节腔中后，基因水凝胶在手术诱导的OA小鼠模型中增加了G5-AHP/miR-140纳米颗粒的保留，防止了关节软骨退化，并减少了骨赘形成。本研究提供了一种新的无细胞方法来缓解OA的进展，显示出局部注射基因递送系统的潜力。
Sustained and controllable local gene therapy is a potential method for treating osteoarthritis (OA) through the delivery of therapeutic microRNAs (miRNAs) to targeted cells. However, direct injection of crude miRNAs for local gene therapy is limited due to its inadequate transfection efficiency, easy inactivation, and short half-life. Here, a multifunctional gene vector, arginine, histidine, and phenylalanine-modified generation 5 polyamidoamine (named G5-AHP), was employed to form G5-AHP/miR-140 nanoparticles by forming a complex with microRNA-140 (miR-140). Then, the nanoparticles were entrapped in hydrogel microspheres (MSs) to construct a "nano-micron" combined gene hydrogel to alleviate the degradation of articular cartilage. Monodisperse gelatin methacryloyl hydrogel MSs were produced under ultraviolet light using one-step innovative microfluidic technology. Evenly dispersed MSs showed better injectability in sustainable and matrix metalloproteinases (MMPs)-responsive degradation methods for local gene delivery. The G5-AHP/miR-140 nanoparticles released from the MSs exhibited high gene transfection efficacy and long-term bioactivity, facilitated endocytosis, and thus maintained the metabolic balance of cartilage matrix by promoting the expression of type II collagen and inhibiting the expression of a disintegrin and metalloproteinase with thrombospondin motifs-5 and MMP13 in chondrocytes. After injection of the "nano-micron" combined gene hydrogel into the articular cavity of the OA model, the gene hydrogel increased G5-AHP/miR-140 nanoparticle retention, prevented articular cartilage degeneration, and reduced osteophyte formation in a surgically induced mouse model of OA. The present study provides a novel cell-free approach to alleviate the progression of OA that shows potential for locally injected gene delivery systems.