Liu Shen, Wu Fei, Gu Shanshan, Wu Tianyi, Chen Shun, Chen Shuai, Wang Chongyang, Huang Guanlan, Jin Tuo, Cui Wenguo, Sarmento Bruno, Deng Lianfu, Fan Cunyi
Department of Orthopaedics Shanghai Jiao Tong University Affiliated Sixth People's Hospital 600 Yishan Road Shanghai 200233 China.
Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine 197 Ruijin 2nd Road Shanghai 200025 China.
Adv Sci (Weinh). 2018 Nov 20;6(2):1801217. doi: 10.1002/advs.201801217. eCollection 2019 Jan 23.
Sustained delivery of small interfering RNA (siRNA) is a challenge in gene silencing for managing gene-related disorders. Although nanoparticle-mediated electrospun fibers enable sustainable gene silencing, low efficiency, loss of biological activity, toxicity issues, and complex electrospinning techniques are all bottlenecks of these systems. Preventing peritendinous adhesion is crucial for their successful use, which involves blocking cellular signaling via physical barriers. Here, a multifunctional, yet structurally simple, cationic 2,6-pyridinedicarboxaldehyde-polyethylenimine (PDA)-mediated extracellular signal-regulated kinase (ERK)2-siRNA polymeric delivery system is reported, in the form of peritendinous antiadhesion electrospun poly-l-lactic acid/hyaluronan membranes (P/H), with the ability to perform sustained release of bioactive siRNA for long-term prevention of adhesions and ERK2 silencing. After 4 days of culture, the cell area and proliferation rate of chicken embryonic fibroblasts on siRNA+PDA+P/H membrane are significantly less than those on P/H and siRNA+P/H membranes. The in vivo results of average optical density of collagen type III (Col III) and gene expression of ERK2 and its downstream SMAD3 in the siRNA+PDA+P/H group are less than those of P/H and siRNA+P/H groups. Consequently, siRNA+PDA+P/H electrospun membrane can protect the bioactivity of ERK2-siRNA and release it in a sustained manner. Moreover, adhesion formation is inhibited by reducing fibroblast proliferation and Col III deposition, and downregulating ERK2 and its downstream SMAD3.
小干扰RNA（siRNA）的持续递送是基因沉默治疗基因相关疾病的一项挑战。尽管纳米颗粒介导的电纺纤维能够实现可持续的基因沉默，但效率低下、生物活性丧失、毒性问题以及复杂的电纺技术都是这些系统的瓶颈。预防腱周粘连对于其成功应用至关重要，这涉及通过物理屏障阻断细胞信号传导。在此，报道了一种多功能但结构简单的阳离子2,6 - 吡啶二甲醛 - 聚乙烯亚胺（PDA）介导的细胞外信号调节激酶（ERK）2 - siRNA聚合物递送系统，其呈腱周抗粘连电纺聚左旋乳酸/透明质酸膜（P/H）的形式，能够持续释放生物活性siRNA以长期预防粘连和ERK2沉默。培养4天后，siRNA + PDA + P/H膜上鸡胚成纤维细胞的细胞面积和增殖率显著低于P/H膜和siRNA + P/H膜上的。siRNA + PDA + P/H组中III型胶原蛋白（Col III）的平均光密度以及ERK2及其下游SMAD3的基因表达的体内结果低于P/H组和siRNA + P/H组。因此，siRNA + PDA + P/H电纺膜能够保护ERK2 - siRNA的生物活性并持续释放它。此外，通过减少成纤维细胞增殖和Col III沉积以及下调ERK2及其下游SMAD3来抑制粘连形成。
