PAI-1 siRNA-loaded biomimetic nanoparticles for ameliorating diminished ovarian reserve and inhibiting ovarian fibrosis

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.