Exosome‐Derived lncRNA LIPE‐AS1 Enhances Oocytes Maturation and Ameliorates Diminished Ovarian Reserve via the miR‐330‐5p/HDAC3 Axis

Diminished ovarian reserve (DOR) is a multifactorial gynecological disorder that has emerged as a significant global health challenge. Currently, there are no effective preventive or therapeutic strategies for DOR. Exosome-derived long non-coding RNAs (lncRNA) in follicular fluid (FF) plays a crucial role in follicular development. We identified exosome-derived lncRNA LIPE-AS1 from the FF of DOR patients, which regulates histone deacetylase 3 (HDAC3) expression by competitively binding to miR-330-5p. Exosomes, as nanosized membrane vesicles, can deliver therapeutic agents in a targeted manner through ligand modification. In this study, we employed engineered exosomes combined with lncRNA for ovary-targeted therapy of DOR. First, we elucidated the role of lncRNA LIPE-AS1 in the pathogenesis of DOR. Next, we generated exosomes with high LIPE-AS1 expression (Exo-LIPE-AS1) using 293 T cells. Co-culture of Exo-LIPE-AS1 with oocytes from DOR models enhanced oocyte maturation and improve oocyte quality in vitro. Finally, we developed FSHβ-modified, LIPE-AS1-loaded exosomes (Exo_FSHβ-LIPE-AS1), which demonstrated enhanced ovarian delivery efficiency in vivo. Consequently, Exo_FSHβ-LIPE-AS1improved fertility outcomes in DOR models. Our findings demonstrate that exosomes serve as effective targeted vehicles for lncRNA LIPE-AS1, offering potential preventive and therapeutic benefits for DOR.