Abstract：
Effective contraceptives have been comprehensively adopted by women to prevent the negative consequences of unintended pregnancy for women, families, and societies. With great contributions of traditional hormonal drugs and intrauterine devices (IUDs) to effective female contraception by inhibiting ovulation and deactivating sperm, their long-standing side effects on hormonal homeostasis and reproductive organs for females remain concerns. Herein, we proposed a nanostrategy for female contraceptives, inducing embryonic trophoblast cell death using nanoparticles to prevent embryo implantation. Cupric oxide nanoparticles (CuO NPs) were adopted in this work to verify the feasibility of the nanostrategy and its contraceptive efficacy. We carried out the in vitro assessment on the interaction of CuO NPs with trophoblast cells using the HTR8/SVneo cell line. The results showed that the CuO NPs were able to be preferably uptaken into cells and induced cell damage via a variety of pathways including oxidative stress, mitochondrial damage, DNA damage, and cell cycle arrest to induce cell death of apoptosis, ferroptosis, and cuproptosis. Moreover, the key regulatory processes and the key genes for cell damage and cell death caused by CuO NPs were revealed by RNA-Seq. We also conducted in vivo experiments using a rat model to examine the contraceptive efficacy of both the bare CuO NPs and the CuO/thermosensitive hydrogel nanocomposite. The results demonstrated that the CuO NPs were highly effective for contraception. There was no sign of disrupting the homeostasis of copper and hormone, or causing inflammation and organ damage in vivo. In all, this nanostrategy exhibited huge potential for contraceptive development with high biosafety, efficacy, clinical translation, nonhormonal style, and on-demand for women.
摘要：
妇女全面采用了有效的避孕药具，以防止意外怀孕对妇女造成负面影响，家庭,和社会。传统激素药物和宫内节育器（IUD）通过抑制排卵和使精子失活，为有效的女性避孕做出了巨大贡献，它们对女性荷尔蒙稳态和生殖器官的长期副作用仍然令人担忧。在这里，我们提出了女性避孕药的纳米策略，使用纳米颗粒诱导胚胎滋养层细胞死亡，以防止胚胎植入。本文采用氧化铜纳米粒子(CuONPs)来验证纳米策略的可行性及其避孕功效。我们使用HTR8/SVneo细胞系对CuONP与滋养层细胞的相互作用进行了体外评估。结果表明，CuONPs能够被较好地吸收到细胞中，并通过包括氧化应激在内的多种途径诱导细胞损伤，线粒体损伤，DNA损伤,细胞周期阻滞诱导细胞凋亡，铁性凋亡,和角化。此外，RNA-Seq揭示了CuONP引起的细胞损伤和细胞死亡的关键调控过程和关键基因。我们还使用大鼠模型进行了体内实验，以检查裸露的CuONP和CuO/热敏水凝胶纳米复合材料的避孕功效。结果表明，CuONP对避孕非常有效。没有迹象表明铜和激素的稳态被破坏,或在体内引起炎症和器官损伤。总之,这种纳米策略在开发具有高生物安全性的避孕药具方面显示出巨大的潜力，功效,临床翻译，非荷尔蒙风格，对女性的需求。
