Ngarande Ellen, Doubell Emma, Tamgue Ousman, Mano Manuel, Human Paul, Giacca Mauro, Davies Neil Hamer
Cardiovascular Research Unit, Department of Surgery, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa.
International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Observatory 7925, South Africa.
Regen Biomater. 2022 Dec 13;10:rbac101. doi: 10.1093/rb/rbac101. eCollection 2023.
RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues. Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers. Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine 3.0, a lipid nonviral transfection vector, for local and sustained release. PEGylation of fibrin allowed for controlled release of small interfering RNA (siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin and . A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days. Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth. Thus, the increased efficacy observed here for the combination of a lipid nanoparticle, the only type of nonviral vector approved for the clinic, with fibrin, might allow for more rapid translation of injectable hydrogel-based RNA interference.
RNA干扰是一种很有前景的治疗方法，但目前受到诸如RNA快速降解和个体组织靶向等递送问题的阻碍。可注射水凝胶是克服这些障碍的一种潜在简单直接的途径。在此，我们报道了将临床使用的纤维蛋白水凝胶的轻度修饰形式与脂质非病毒转染载体Invivofectamine 3.0相结合用于局部和持续释放的效用。纤维蛋白的聚乙二醇化允许小干扰RNA（siRNA）-脂质多聚体的控释至少10天，并大大提高了纤维蛋白的稳定性。一个三维细胞培养模型和一项释放研究表明，siRNA-脂质多聚体的转染效力至少保持7天。与聚乙二醇化纤维蛋白原联合注射显著增加了siRNA-脂质多聚体在小鼠骨骼肌中的滞留，并增强了与肌肉生长相关的肌肉生长抑制素mRNA的敲低。因此，此处观察到的脂质纳米颗粒（唯一一种被批准用于临床的非病毒载体类型）与纤维蛋白组合的疗效提高，可能会使基于可注射水凝胶的RNA干扰更快地转化应用。
