FSHR-targeting tetrahedral DNA frameworks ameliorate ovarian aging through oxidative stress elimination

Ovarian aging, characterized by declining ovarian reserve, is a pacemaker of aging in the female body. Oxidative stress leads to apoptosis, mitochondrial dysfunction, inflammation, and telomere shortening, accelerating ovarian aging. Scavenging reactive oxygen species (ROS) has been shown to delay ovarian aging; however, there remains a significant lack of antioxidants with both proven efficacy and minimal side effects. DNA tetrahedral nanostructure (DTN) is a promising nucleic acid framework with antioxidant and anti-apoptotic properties. We developed FSH-DTN, a modified nanoparticle equipped with a follicle-stimulating hormone receptor-targeting peptide (FSH33-53) to enhance ovarian accumulation. Compared to native DTN, FSH-DTN showed superior ovarian targeting efficiency as confirmed by in vivo imaging. In both in vivo and in vitro models of acute, subacute, and chronic ovarian aging, FSH-DTN demonstrated superior antioxidant, anti-apoptotic, and anti-aging effects. Further investigation revealed that FSH-DTN can directly eliminate ROS in the ovaries while enhancing ovarian antioxidant capacity by activating the NRF2 signaling pathway, thereby protecting ovarian function. In this study, we offer a new strategy for neutralizing oxidative stress to delay ovarian aging.