Nanomotor‐Driven Extracellular Vesicles With Effective Tissue Penetration for Targeted Therapy of Primary Ovarian Insufficiency

Stem cells and their derived extracellular vesicles (EVs) offer hope for functional reconstruction and fertility in premature ovarian insufficiency (POI) caused by gonadotoxic drugs. However, the clinical application of EVs is impeded by their instability, limited tissue penetration, and lack of targeted delivery to ovarian injury sites. Here, we introduce an injectable hydrogel loaded with nanomotor-driven EVs (LEVs-Gel) for targeted POI therapy. In the POI ovarian microenvironment, reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) are highly expressed, acting as chemoattractants to promote the chemotactic behavior of nanomotors LEVs. The LEVs are loaded in a thermosensitive hydrogel to enhance the retention and stability of EVs at the ovary. Following local injection of LEVs-Gel into the ovaries of POI mice, the nanomotors LEVs effectively penetrated the epithelial layer and the tunica albuginea, significantly enhancing the permeability of the cortical and medullary regions. This intervention successfully restored ovarian endocrine and reserve functions, thereby improving reproductive fertility. Further mechanistic studies revealed that the therapeutic efficacy of LEVs-Gel is mediated through the maintenance of oxidative-antioxidative balance, inhibition of apoptosis, and promotion of ovarian angiogenesis. Overall, this integrated therapy presents a promising targeted strategy for patients with POI caused by chemotherapy.