Currently, hormonal therapy for endometriosis faces challenges in achieving a balance between treatment and preserving the chance of pregnancy. Therefore, the development of non-hormonal therapy holds significant clinical importance. Angiogenesis is a hallmark of endometriosis, and anti-angiogenic therapies targeting the hypoxia-inducible factor-1α (HIF-1α) pathway are considered potential approaches for endometriosis. However, angiogenesis is also involved in numerous physiological processes, including pregnancy, and systemic anti-angiogenesis may lead to severe adverse effects. To address this, a cRGD-modified liposome nanodrug (cRGD-LP-ART) is synthesized, which enhances drug efficacy while reducing adverse reactions. Artesunate (ART), a non-hormonal drug used to treat malaria, has shown anti-angiogenic effects beyond its original indications in various benign and malignant diseases. With cRGD modification, cRGD-LP-ART can target ectopic lesions and inhibit local angiogenesis by suppressing the HIF-1α/vascular endothelial growth factor (VEGF) pathway. Furthermore, cRGD-LP-ART exhibits better therapeutic effects than free ART, without affecting ovarian function or causing atrophy of the eutopic endometrium, making it a promising new option for non-hormonal therapy of endometriosis. As a combination of liposomes and a clinically approved drug, cRGD-LP-ART holds great potential and clinical prospects for the treatment of endometriosis.
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.
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