Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China; Ningxia Medical University, Yinchuan, Ningxia, 750004, China.
College of Biology, Hunan University, Changsha, 410082, China.
Eur J Pharmacol. 2024 Nov 15;983:176948. doi: 10.1016/j.ejphar.2024.176948. Epub 2024 Aug 30.
With specific and inherent mRNA cleaving activity, small interfering RNA against pro-fibrosis factor (PAI-1 siRNA, siPAI-1) has demonstrated the fucntion for preventing diminished ovarian reserve (DOR). Moreover, safe nanomaterials have provided ideal tools for delivering siRNA to the targeted cells to obtain high therapeutic efficacy. In order to improve the preventing capability of siPAI-1 for DOR, we synthesized one kind of biomimetic Poly (lactic-co-glycolic acid) copolymer (PLGA)-based nanoparticles (siPAI-1@PLGA@M-FSHL, abbreviated as SPMF). siPAI-1 was assembled into cationic PLGA nanoparticles, following with macrophage membrane coating (M) and FSHL81-95 peptide modification. SPMF NPs significantly enhanced cellular uptake and gene silencing efficiency in KGN cells in vitro. In vivo assay demonstrated that SPMF NPs can targetedly accumulate in the ovarian of DOR mice with Cyclophosphamide treatment (80 mg/kg/week, 2 weeks) and remarkably downregulate the levels of PAI-1 in ovarian, which finally resulted in the effective suppression of ovary fibrosis and improved the chemotherapy-induced follicle loss to increase the number of primordial, secondary, antral follicles by 62.05 %, 54.92 % and 64.37 %, respectively, compared with DOR group. In summary, this study demonstrates that siPAI-1-loaded SPMF with high safety and efficacy can potentially alleviate DOR by inhibiting the overexpression of PAI-1 in the ovarian.
具有特定和固有 mRNA 切割活性的抗纤维化因子小干扰 RNA（PAI-1 siRNA，siPAI-1）已被证明具有预防卵巢储备减少（DOR）的功能。此外，安全的纳米材料为将 siRNA 递送到靶向细胞以获得高治疗效果提供了理想的工具。为了提高 siPAI-1 预防 DOR 的能力，我们合成了一种仿生聚（乳酸-共-乙醇酸）共聚物（PLGA）基纳米颗粒（siPAI-1@PLGA@M-FSHL，简称 SPMF）。siPAI-1 被组装到阳离子 PLGA 纳米颗粒中，随后进行巨噬细胞膜包被（M）和 FSHL81-95 肽修饰。SPMF NPs 显著提高了 KGN 细胞中细胞摄取和基因沉默效率。体内实验表明，SPMF NPs 可以靶向积聚在环磷酰胺处理（80mg/kg/周，2 周）的 DOR 小鼠的卵巢中，并显著下调卵巢中 PAI-1 的水平，最终有效抑制卵巢纤维化，并改善化疗诱导的卵泡丢失，使原始卵泡、次级卵泡和窦卵泡的数量分别增加 62.05%、54.92%和 64.37%，与 DOR 组相比。总之，这项研究表明，载有 siPAI-1 的 SPMF 具有高安全性和疗效，可通过抑制卵巢中 PAI-1 的过度表达来潜在缓解 DOR。
