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FSHR-targeting tetrahedral DNA frameworks ameliorate ovarian aging through oxidative stress elimination
Yun Dai1,2,3, Yican Guo1,2,3, Dan Chen1,2,3
1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
Abstract:
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.
Insights
This study introduces FSH-DTN, a novel nanoparticle that targets the ovaries to combat oxidative stress and delay ovarian aging. It demonstrates superior antioxidant and anti-aging effects, offering a new strategy for preserving ovarian function.
Area of Science:
- Reproductive biology
- Gerontology
- Nanomedicine
Background:
- Ovarian aging, marked by reduced ovarian reserve, accelerates female aging.
- Oxidative stress drives ovarian aging through apoptosis, mitochondrial dysfunction, and inflammation.
- Existing antioxidants lack proven efficacy and have side effects, necessitating novel solutions.
Purpose of the Study:
- To develop and evaluate FSH-DTN, a targeted nanoparticle for ovarian delivery.
- To assess FSH-DTN's efficacy in mitigating oxidative stress and delaying ovarian aging.
- To elucidate the mechanisms underlying FSH-DTN's protective effects on ovarian function.
Main Methods:
- Development of FSH-DTN, a DNA tetrahedral nanostructure with a follicle-stimulating hormone receptor-targeting peptide.
- In vivo imaging to confirm ovarian targeting efficiency of FSH-DTN.
- In vitro and in vivo models of acute, subacute, and chronic ovarian aging to evaluate FSH-DTN's effects.
- Analysis of ROS scavenging, apoptosis, NRF2 pathway activation, and ovarian function.
Main Results:
- FSH-DTN exhibited enhanced ovarian accumulation compared to native DTN.
- FSH-DTN demonstrated significant antioxidant, anti-apoptotic, and anti-aging effects in ovarian aging models.
- FSH-DTN directly scavenged reactive oxygen species (ROS) and activated the NRF2 pathway, boosting endogenous antioxidant capacity.
- Ovarian function was protected by FSH-DTN treatment.
Conclusions:
- FSH-DTN is a promising nanotherapeutic for targeting ovarian aging.
- This targeted nanoparticle effectively neutralizes ovarian oxidative stress.
- FSH-DTN represents a novel strategy to delay ovarian aging and preserve reproductive health.
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