Premature ovarian failure (POF), a major cause of female infertility characterized by disturbed hormone levels, defective follicular development and abnormal ovarian reserve, remains a significant medical challenge. Antioxidation is considered as one of the most promising treatments for POF, while even the super strong antioxidants (e.g. melatonin, coenzyme Q10 and astaxanthin) have limited therapeutic effects and the underlying mechanism remains ambiguous. Herein, a dietary antioxidant nanodrug was developed for POF treatment by entrapping vitamin C into cross-linked lipoic acid vesicles (VC@cLAV). Although the VC@cLAV’s reactive oxygen species (ROS) scavenging efficiency in solution was similar with melatonin (the gold standard antioxidant for POF treatment), its intracellular antioxidation duration time was much longer than that of melatonin, which made the VC@cLAV to produce highly satisfactory therapeutic effects on both chemotherapy-induced and natural aging POF models. In the further mechanism study, we identified for the first time WNT7A/CYP19 as the crucial signaling pathway in the treatment, whose sustained activation improved the cytochrome P450 family 19 (CYP19)-dependent gonadal hormone metabolism in granulosa cells (GCs), and then recovered the ovarian reserve function. This study reveals the essence of antioxidation treatment of POF, and provides a new strategy for POF therapy.