Exosome-Derived lncRNA LIPE-AS1 for Enhancing Oocytes Maturation and Ameliorating Diminished Ovarian Reserve through Targeting miR-330-5p/HDAC3 Axis

Abstract Diminished ovarian reserve (DOR) is a multi-factor gynecological disease that has become a major global health problem. Currently, there is no effective prevention and therapy for DOR. Exosome-drived long non-coding RNAs (lncRNA) in follicular fluid (FF) plays a vital role in development of follicles. Exosome-drived lncRNA LIPE-AS1, which we screened from FF of patients with DOR, regulates histone deacetylase 3 (HDAC3) expression by competitively inhibiting miR-330-5p. Exosomes as nanosized membrane vesicles, could targeted deliver therapeutic agents by modification with target ligands. In this study, we utilize the engineering tochnology to conbime exosome and lncRNA for ovary-targeting therapy of DOR. Firstly, we elucidated the mechanism of lncRNA LIPE-AS1 in occurrence and development of DOR. Secondly, we biologically prepared the exosomes with LIPE-AS1 high expression using 293T cells (Exo-LIPE-AS1). Co-culture of Exo-LIPE-AS1 with oocytes of DOR models promotes oocyte development and improve oocyte quality in vitro. Last, we constructed the FSHβ-modified and LIPE-AS1 loaded exosomes (ExoFSHβ-LIPE-AS1). The engineered exosomes ExoFSHβ-LIPE-AS1 could deliver more efficiently to ovary in vitro. In this way, ExoFSHβ-LIPE-AS1 facilitate the fertility of DOR models. Our research elucidates that exosomes as targeted lncRNA LIPE-AS1 delivery vehicles have potentially preventive and therapeutic effects for DOR.