Rethinking the application of nanoparticles in women's reproductive health and assisted reproduction

Nanoparticles and nanotechnology may present opportunities to revolutionize the prevention, treatment and diagnosis of a range of reproductive health conditions in women. These technologies are also used to improve outcomes of assisted reproductive technology. We highlight a range of these potential clinical uses of nanoparticles for polycystic ovary syndrome, endometriosis, uterine fibroids and sexually transmitted infections, considering in vitro and in vivo studies along with clinical trials. In addition, we discuss applications of nanoparticles in assisted reproductive technology, including sperm loading, gamete and embryo preservation and preventing preterm birth. Finally, we present some of the concerns associated with the medical use of nanoparticles, identifying routes for further exploration before nanoparticles can be applied to women’s reproductive health in the clinic.

: assisted reproductive technology, endometriosis, nanoparticles, polycystic ovary syndrome, sexually transmitted infections, uterine fibroids, women’s reproductive health Tweetable Abstract What opportunities do nanoparticles present to revolutionize the prevention, treatment and diagnosis of reproductive health conditions in women and improve outcomes of assisted reproductive technology? Plain language summary Executive summary. Polycystic ovary syndrome Metal nanoparticles can exhibit direct effects on polycystic ovary syndrome, reducing insulin resistance and inflammation. Lipid-based nanoparticles significantly increase the bioavailability of existing polycystic ovary syndrome treatment drugs. Endometriosis Nanoparticles provide a possible nonsurgical route for endometriosis diagnosis, while also potentially linking lesion identification and treatment through coupling imaging agents to nanoparticles with high heating efficiency to induce local hyperthermia. Endometriosis-related inflammation, oxidative stress and angiogenesis have all been reduced in animal endometriosis models by the addition of nanoparticles. Uterine fibroids Nanoparticles aid both in traditional treatment methods (as an embolic material) and in the delivery of interfering peptides, nucleic acids and drugs that can reduce fibroid size. Sexually transmitted infections Nanoparticles may allow the rapid diagnosis of sexually transmitted infections such as gonorrhea and chlamydia through gold nanoparticle biosensors. Nanoparticles can improve traditional contraceptive methods: silver nanoparticles, exhibiting antimicrobial effects, can be used to coat condoms or to reduce biofilm formation on intrauterine devices. Nanoparticles may be an effective way to formulate vaccinations against sexually transmitted infections due to their in vivo trafficking, ability to present multimeric antigens and enhanced immunogenic responses. Sperm loading Magnetic nanoparticles and mesoporous silica nanoparticles have been successfully used to interact with sperm and also to carry biological factors such as nucleic acids and proteins. This may allow missing or defective factors to be replaced during assisted reproductive technology to aid fertility. Gamete/embryo preservation Oxidative stress induced by cryopreservation of gametes can be reduced by the use of nanoparticles either as part of the freezing medium or via membrane-lipid replacement. Nanoparticles increase the heating efficiency of cryopreserved gametes and embryos in a safe and effective manner. The application of nanotechnology to the field of medicine has the potential to improve the treatment and diagnosis of many medical conditions. Nanoparticles have many unique features that render them especially suitable for a variety of purposes, including controlled drug delivery, labeling and direct functionality [1]. Nanotechnological approaches have already been implemented in a range of biomedical applications, with nanomaterials used in the clinic as drug-delivery systems with clear benefits over a free drug [1], such as reduced toxicity and degradation while improving bioavailability and accumulation at the target site. The vast majority of research into nanoparticles has focused on their applications in the diagnosis and treatment of cancer [2], with good clinical success [3]; however, there is also significant potential for their application in other disciplines, from regenerative medicine [2] to the diagnosis and treatment of reproductive health conditions, and also in assisted reproductive techniques. Women’s reproductive health conditions traditionally face challenges in diagnosis and often do not have effective treatment pathways. The growing field of nanomedicine may provide new opportunities for minimally invasive diagnostic approaches. Additionally, nanoparticles may allow enhanced storage and manipulation of gametes; gametes are not easy to penetrate, and so the unique properties of nanoparticles pose an exciting opportunity to improve the outcomes of assisted reproductive techniques. This review explores the many roles that nanotechnology plays, and may potentially play, in the diagnosis and treatment of a selection of reproductive and sexual health concerns in women. We also investigate the possibility of using nanotechnology to facilitate assisted reproductive technology (ART) and the potential ways in which nanoparticles could provide novel solutions for infertility. Reproductive health A variety of nanotechnology approaches have been applied to a range of reproductive health issues in women, as shown in Table 1 & Supplementary Table 1. Table 1. | Condition | Application | Author(s) | Ref. | | |---|---|---|---|---| | Polycystic ovary syndrome | Detection | Roth et al., Hu et al., Li et al. | [4–6] | | | Inflammation reduction | Rabah et al., Alwan et al., Xie et al., Zhao et al., Zhao et al. | [7–11] | || | Increasing drug bioavailability | Raja et al., Fatemi Abhari et al., Salem et al. | [12–14] | || | Increasing insulin sensitivity | Butt et al., Rabah et al., Park et al., Cao et al. | [7,15–17] | || | Endometriosis | Detection | Exosome signature | Khalaj et al. | [18] | | MRI | Lee et al., Zhang et al. | [19,20] | || | Photoacoustic labeling | Marquadt et al. | [21] | || | Immunosensing | Sangili et al., Kalyani et al. | [22,23] | || | Pain management | Yuan et al. | [24] | || | Gene therapy | Zhao et al., Zhao et al., Chaichian et al. | [25–27] | || | Inflammation reduction | Davoodi Asl et al., Wu et al., Chaudhury et al., Sun et al., Bedin et al., de Almeida Borges, Liu et al. | [28–34] | || | Sustained drug release | Boroumand et al., Sun et al. | [35,36] | || | Thermal therapy | Moses et al., Park et al. | [37,38] | || | Uterine fibroids | Increasing drug bioavailability | Ali et al., Enazy et al., El Sabeh et al. | [39–41] | | | Delivering viral gene therapy vectors | Shalaby et al., Egorova et al., Shtykalova et al. | [42–44] | || | Embolic agent | Choi et al. | [45] | || | Gonorrhea | Diagnosis | Liu et al., Chen et al. | [46,47] | | | Vaccination | Rodrigues et al., Wang et al., Gala et al. | [48–50] | || | Human immunodeficiency virus | Prevention | Mohammed Fayaz et al., Yah et al., Nunes et al., Notario-Perez et al. | [51–54] | | | Vaccination | Murji et al., Li et al., Cohen et al. | [55–57] | || | Herpes simplex | Prevention | Ensign et al. | [58] | | | Vaccination | Awasthi et al. | [59] | || | Human papillomavirus | Vaccination | Rezaei et al. | [60] | Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder affecting an estimated 8% of women and is the suspected cause of up to 40% of cases of female infertility [61]. PCOS is also considered a leading cause of reproductive cancers, including endometrial carcinoma, and is also likely to cause anovulation [62]. There are several challenges associated with PCOS in the clinic, including delayed diagnosis, diagnostic challenges and a lack of clear treatment pathways [63]. Nanoparticles have the potential to aid in both the diagnosis and treatment of PCOS [64]; their small size (10–1000 nm) and ability to carry metal and semiconductor materials, such as gold, silver and ferric oxide, can facilitate contrast for imaging, or by directly delivering these bioactive particles to cells and tissues [65]. Lipid carriers have also been produced on the nanoscale and have several advantages: the lipids chosen are well tolerated by the human body, they are highly stable and they can carry both hydrophilic and lipophilic compounds to target tissues, while also minimizing the dose required due to targeted delivery [66]. Additionally, nanocarriers are produced by cells in vivo which could be harnessed for use in the clinic. Exosomes are a category of extracellular vesicles produced by cells with a diameter of approximately 100 nm [67]. Cell-derived exosomes can carry a range of biomolecules as cargo, including lipids, nucleic acids, amino acids and cell metabolites. Developing nanoparticles for use in the clinic will allow the fine-tuning of key parameters such as immunogenicity, release rate, solubility and half-life in the bloodstream, thus optimizing delivery options for each cargo and target (Figure 1). Diagnosis The current diagnostic process requires the presence of two of the three diagnostic criteria: oligo/anovulation, androgen excess and ultrasound assessment of ovarian morphology, along with exclusionary tests for hyperprolactinemia, thyroid disease and congenital adrenal hyperplasia, among other conditions [63]. Nanoparticles themselves may be suitable biomarkers that can aid in the diagnosis of PCOS. Recent studies have found that the small noncoding RNAs carried in follicular fluid exosomes are markedly different between PCOS patients and non-PCOS groups and should be explored further as a possible biomarker for diagnostic techniques [4,5]. Exosome detection requires high precision, and so emerging techniques such as surface-enhanced Raman spectroscopy, which has recently gained attention for its possible application in exosome-based diagnostics of cancers, may become useful for PCOS diagnosis [6]. Treatment Nanotechnology offers a range of possible treatments for PCOS. This condition is frequently linked to obesity in women due to the cross-talk between PCOS, insulin resistance and obesity. In particular, insulin signaling is likely to be impaired via the PI3K/Akt pathway [68]. Selenium nanoparticles (SeNPs) have been investigated as a potential treatment for endocrine and reproductive dysfunction in a rat model of letrozole-induced PCOS [15]. SeNPs improved glycemic control, eliciting insulin-like effects by activating Akt and other kinases in the insulin signaling cascade, thus increasing insulin sensitivity. In addition, the SeNPs also exhibited significant anti-inflammatory activity in the ovaries and had a greater effect when combined with metformin [7]. This early study highlighted the possibility of using SeNPs as a direct treatment for PCOS. Additionally, in 2023, SeNPs were shown to modulate the expression levels of the androgen receptor, which are elevated in PCOS, thus reducing expression to almost the levels seen in the control group [69]. Another study showed that silver nanoparticles reduced the levels of inflammatory cytokines in rats with PCOS, with the levels of TNF-α, IL-6 and IL-18, cytokines associated with PCOS [70,71], all being significantly lower in rats treated with Cinnamomum zeylanicum-derived silver nanoparticles than in the control [8]. There is also hope that extracellular vesicles derived from mesenchymal stem cells may prove to be a viable treatment for PCOS [72]. Mesenchymal stem cells are being investigated in a number of regenerative medicine applications due to their ability to inhibit inflammation, including in PCOS, helping to relieve ovarian dysfunction [9]. While the research is still limited, there are early results from in vitro human cell studies and mouse models of PCOS that used exosomes to upregulate miR-323-3p expression in cumulus cells, reducing apoptosis and aiding cell proliferation [10]. Additionally, exosomes derived from human umbilical cord mesenchymal stem cells have been shown to inhibit inflammation in ovarian granulosa cells [11]. Studies testing mesenchymal stem cell-derived exosomes on rodent models of PCOS found that not only did this treatment reverse PCOS-related metabolic changes but it also restored ovarian function and fertility [16,17]. Exosome-based treatments are advantageous over whole-cell treatments as they reduce the risk of rejection by the immune system and also reduce the cost and increase accessibility to treatment. These studies have far to go before exosomes can be used in clinics, but may eventually provide another line of treatment for PCOS. Nanoparticles may also be employed to enhance the bioavailability of existing PCOS treatments. Curcumin is known to be an effective anti-inflammatory. Self-assembled curcumin-encapsulated nanoparticles with modified chitosan were successful in increasing the uptake of curcumin when compared with curcumin as a free drug and also led to the recovery of the estrous cycle in rats with PCOS [12]. This is an exciting prospect for potential drug-based management of this disease. An alternative nanoparticle-based curcumin delivery method, using curcumin-loaded superparamagnetic iron oxide (SPIO; Fe3O4), demonstrated significant benefits in a mouse model of PCOS by acting as an antioxidant and by reducing the expression of several apoptosis-inducing factors [13]. Nanovesicle transethosomes have also been used to improve the delivery of progesterone, which has low bioavailability due to poor solubility and hepatic metabolism. Transethosomes are flexible lipid vesicles that can enhance permeation, particularly through the vaginal mucosa, making them suitable to act as a delivery vehicle for progesterone. In human trials, this vaginal gel formulation increased endometrial thickness along with pregnancy rate in anovulatory PCOS patients [14]. There is also scope for the production of synthetic exosomes that could carry these active pharmaceutical ingredients, which may cause fewer side effects [73]. Overall, enhanced bioavailability may provide several different treatment options to restore a typical menstrual cycle to patients with PCOS. Endometriosis Endometriosis is another common women’s reproductive health condition plagued by diagnostic and therapeutic challenges. Endometriosis is estimated to affect 11% of all women [74] and is an inflammatory chronic pain condition in which uterine tissue grows outside of the uterus. It is characterized by symptoms of abnormal periods, infertility and pain. At present, major surgery – usually an exploratory laparotomy – is required to confirm endometriosis at the histological level; however, this causes a significant delay in diagnosis such that the average wait from the onset of symptoms to diagnosis is more than 7 years [75]. Diagnosis Nanoparticles could provide several alternative diagnostic pathways, including some that do not require surgery [76]. The potential use of extracellular vesicles in both diagnosis and treatment for endometriosis has recently been well-reviewed [77]; they show great potential, despite research currently being limited to animal models. As with PCOS, an RNA signature found in endometriosis patients’ exosomes has been identified, with unique microRNAs and long noncoding RNAs, which could theoretically be used as a biomarker to aid in diagnosis, requiring a biopsy rather than exploratory surgery for a diagnosis [18]. Nanoparticles have been successful in enhancing the MRI detection of endometriosis in a rat model. Although MRI can be used for the diagnosis of endometriosis, its sensitivity for deep pelvic endometriosis can be as low as 76% [78]. The intravenous delivery of ultrasmall SPIOs is followed by their efficient uptake by macrophages, which are abundant in the peritoneal cavity of women with endometriosis. Ultrasmall SPIOs can then act as an effective MRI contrast agent, identifying regions of ectopic uterine tissue that are indicative of endometriosis [19]. Magnetic iron oxide nanoparticles modified with hyaluronic acid have also been shown to clearly define lesion margins in a rat model of endometriosis [20]. These studies require further development before this strategy can be applied diagnostically in humans. Rats do not spontaneously develop endometriosis, and the surgically induced rat endometriotic lesions may not behave in the same manner as endometriotic tissue in humans [79]; however, these possibilities should certainly be investigated for their potential application in humans. Immunosensors are another option for the nanoparticle-based detection and diagnosis of endometriosis. Nanoparticle-based immunosensors can be used to identify biomarkers of endometriosis in the blood. CA 125 is the primary serum marker for late-stage endometriosis; a previous study synthesized a sensor made from a nanocomposite of conductive gold nanoparticles and reduced graphene oxide with an immobilized antibody for CA 125 attached. This immunosensor successfully detected CA 125 in blood samples acquired from patients with endometriosis [22]. Another immunosensor based on nanoparticle technology has also been developed, involving a bionanocomposite of a multiwalled carbon nanotube and magnetite nanoparticles in chitosan providing a surface to immobilize a monoclonal antibody for the sensing of carbohydrate antigen 19-9, another candidate marker for endometriosis. This sensor showed high levels of sensitivity and may be suitable for early-stage diagnosis and the monitoring of disease progression [23]. Photoacoustic labeling, using gold nanoparticles as a contrast agent, has shown promise as a new noninvasive imaging method. This approach has been successfully used to image breast cancer cells without antibodies or complex nanoparticle surface modifications [80]. The use of gold nanoparticles as an exogenous contrast material, along with endogenous photoacoustic signals such as hemoglobin, allows the location of endometriosis-like lesions within the peritoneal cavity [21]. This provides significant hope for noninvasive clinical imaging, which could be beneficial for a range of conditions. This strategy could streamline the diagnostic pathway for endometriosis, although there is a need for a significant amount of preclinical development before this can become a reality. Treatment There is no current treatment that can cure endometriosis; therefore, medications focus instead on managing the condition and its symptoms. Currently, pain management medication, hormone management through contraceptives, surgery to remove endometrial tissue and hysterectomy are all used to improve the quality of life of patients [81]. However, endometriosis can reoccur frequently, thus requiring further surgery [82]. Furthermore, these methods may also compromise fertility. Fertility preservation is among the top ten research priorities for endometriosis in the UK and Ireland following a survey targeted to women with endometriosis [83], with almost half of infertile women with normal ovulation and normospermic partners being diagnosed with the condition according to a 2009 retrospective case series [84]. Nanoparticles may increase the efficacy of current endometriosis management techniques. P2X3, an ATP-gated ion channel, may be implicated in endometriosis pain. Chitosan oligosaccharide-g-stearic acid polymer micelles-coated nanostructured lipid carriers have been developed as a delivery system for a selective P2X3 receptor antagonist, A-317491; this treatment strategy induced a reduction of hyperalgesia in both endometriotic mice and rats [24]. Exosomes may pose another possible treatment strategy for endometriosis. Exosomes derived from menstrual blood mesenchymal stem cells in preliminary cell-based studies were shown to reduce apoptosis, inflammation, proliferation and angiogenesis markers, reducing lesion-forming behavior [28]. Exosomes enriched with miR-214 from endometrial cells were also shown to reduce connective tissue growth factor in endometriosis xenograft mouse models, which is implicated in fibrogenesis in endometriosis (Figure 2) [29]. Both of these may be able to reduce inflammation, potentially reversing some of the effects of this chronic reproductive health condition. Nucleic acids may also be delivered by synthetic nanoparticles in targeted therapies to modulate essential gene expression in endometriosis tissue. Chitosan oligosaccharide stearic acid micelles have been investigated as delivery vehicles for nucleic acids, particularly for siRNAs [85], due to their nontoxic and biodegradable properties and their ability to protect highly electronegative nucleic acids and facilitate cell entry. siRNAs have been investigated for the treatment of endometriosis by knocking down the expression of AQP2, which is known to support endometrial tissue migration, invasion and adhesion [86]. Chitosan oligosaccharide stearic acid micelles with polyethylenimine and hyaluronic acid and loaded with siRNAs targeted to AQP2-suppressed endometriotic lesion formation in a rat model of endometriosis while showing no adverse effects on the reproductive organs [25]. This approach has also been successful in gene therapy, introducing the gene encoding PEDF, a serine protease that is associated with the inhibition of angiogenesis and tumorigenesis; this led to a significant increase in apoptosis and a reduction in angiogenesis [26]. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles have also been used as a delivery vehicle for miRNAs to promote apoptosis in endometriotic cells. miR-503 is implicated in the apoptosis of endometriotic cyst stromal cells and prevents cell proliferation. In experiments involving human endometriotic tissue, miR-503-loaded PLGA nanoparticles caused an increase in apoptosis and a decrease in cell proliferation [27]. Cerium oxide nanoparticles have been shown to reduce endometriotic lesions that were induced in a mouse model by reducing oxidative stress and angiogenesis [30]. These nanoparticles act as free radical scavengers and can reduce the levels of reactive oxygen species (ROS) in vivo, thus inhibiting VEGF expression. Anti-inflammatory therapies using nanoparticles have also been investigated, such as acid-sensitive calcium carbonate nanoparticles associated with BML-11. This type of nanoparticle releases calcium and BML in an acidic environment; the resulting increase in local calcium concentration upregulated both apoptosis and efferocytosis in a mouse model of endometriosis, while also showing no severe side effects and strong biosecurity [31]. Rapidly dividing tumorigenic cells, including endometriotic cells, require the uptake of low-density lipoprotein. Low-density lipoprotein receptor mRNA has been shown to be overexpressed in endometriotic lesions [87]. Lipid nanoparticles have been developed to exploit this event, targeting these cells and delivering a coupled chemotherapeutic agent [32]. These nanoparticles have been tested in a preliminary study which showed that this approach lacked systemic side effects and could provide a treatment option for endometriosis that avoids surgery [32]. Nanofibers have also been explored as a drug-delivery system for the prolonged release of medication in the form of an implantable, cargo-carrying scaffold. This prolonged release is especially useful for conditions such as endometriosis that have a high chance of recurrence following surgical removal. The implantation of polycaprolactone–PEG nanofibers loaded with curcumin in the peritoneum of mice successfully reduced the size of endometriotic tissue and regions of inflammation when compared with a control group that received no treatment [35]. Furthermore, these nanofibers also continued to release the drug over a significant period of time, with 50% of the curcumin released after 30 days. Other formulations of nanofibers have been tested but have not demonstrated such long-term release of their drug cargo [36]. Nanoparticles may also aid in physically locating and removing endometriotic tissue. Photothermal therapy is a novel strategy for disease treatment in which photothermal agents convert near-infrared light into heat to induce local cell death due to elevated temperature [88]. In a previous study, Moses et al. developed a nanoplatform that could both identify and ablate endometriotic tissues using near-infrared fluorescence and photothermal therapy [37]. This nanoplatform used a polymeric nanoparticle as a carrier for silicon naphthalocyanine, a photothermal agent that accumulates in endometriotic tissue. When activated by near-infrared light, the nanoparticles heat tissue to 53°C in vitro and 47°C in endometriotic grafts, thus causing cell death and removing the endometriotic tissue. This platform has significant potential for streamlining the process of lesion identification and surgical removal into a single procedure, although much progress is required in preclinical trials before this can become a reality in the clinic. Magnetic hyperthermia has also been investigated as an alternative therapy for endometriosis. Iron oxide-based magnetic particles with high heating efficiency were generated and encapsulated by PEG-block–poly(ϵ-caprolactone)-based nanocarriers to overcome the hydrophobicity of the magnetic particles alone. When activated, these nanoparticles heated endometriotic lesions to 51.6°C. There is also scope for the addition of specific ligands to target overexpressed receptors found on endometriotic cells, further targeting the nanoparticles to endometriotic tissue and avoiding healthy tissue [38]. Other uses of nanoparticles for the treatment of endometriosis are currently under investigation, including copaiba-oil resin encased in polyvinylpyrrolidone polymer, which successfully reduced inflammation and proliferation [33]; neutrophil-mediated delivery of nanoparticles [89]; and antibodies to modulate immune activity encased in PLGA [34]. These findings provide significant hope that we may discover a more effective treatment for endometriosis (Figure 3). Uterine fibroids Uterine fibroids are the most common benign tumor of the female reproductive system. These are hormone-dependent tumors arising from the myometrium, with an estimated cumulative incidence of 70–80% [90]. These tumors can cause pelvic pain, infertility, pregnancy complications and menorrhagia, as well as further complications during childbirth [91]. Surgery and hormonal therapy can be successful but the effects are only temporary; furthermore, these options are unsuitable for women who would like to conceive [92]. The pathology of uterine leiomyoma includes extracellular matrix remodeling and accumulation, thus providing a potential drug target for specific therapies [93]. 2-methoxyestradiol (2-ME), a promising anticancer agent that acts as an angiogenesis inhibitor, was previously loaded into nanoparticles and proved to be highly successful when tested in vitro against human leiomyoma cells [39]. 2-ME has previously been shown to be a potent antitumorigenic agent suitable for uterine leiomyoma cells, with antiangiogenic, antiproliferative, proapoptotic and collagen synthesis inhibitory properties [94]; however, 2-ME has low bioavailability due to its poor aqueous solubility, thus posing a challenge when administering the drug [95]. The polymeric liposomal nanoparticles in this study significantly improved bioavailability and induced cytotoxicity far more successfully than the free drug. PEGylated polymeric nanoparticles with 2-ME cargo led to a 51% inhibition in the growth of xenografted patient-derived human fibroid tumors in mice when compared with a control group [40], thus providing further evidence that this may represent a novel method for treating uterine leiomyoma. Magnetic nanoparticles loaded with viral cargo have also demonstrated potential success for the nonsurgical treatment of uterine fibroids. The possibility of nanotechnology-enabled gene therapy has been investigated in in vitro studies by the application of magnetic nanoparticles complexed to an adenovirus [42]. These conjugates led to an increase in the efficiency of targeted suicidal gene transfer into tumor cells when compared against nonconjugated adenovirus. The magnetic properties of these nanoparticles permit molecules to be concentrated at their required sites by using external magnetic fields, thus promoting cellular uptake. However, reducing the effective dose of adenoviral vectors is critical if this method of gene therapy is to be translated to the clinic. Peptide-based nanoparticles provide an alternative route to gene therapy that is less likely to stimulate a detrimental immune response. Ligand-modified nanoparticles of polycondensed arginine–histidine-rich oligomers modified with iRGD, a tumor-penetrating peptide, were shown to be successful in herpes simplex virus (HSV) thymidine kinase gene delivery to uterine leiomyoma cells; followed by ganciclovir treatment, this treatment significantly reduced the proliferation of leiomyoma cells [43]. A similar suicide gene therapy approach has been achieved with magnetic cationic nanoparticles targeting the delivery of HSV thymidine kinase, increasing delivery efficiency while reducing the time taken for successful transfection in primary human uterine leiomyoma cells [44]. Further in vitro studies showed that simvastatin induces calcium-dependent apoptosis in human uterine leiomyoma cells, while also inhibiting proliferation by inhibiting ERK phosphorylation in the growth factor signaling pathway [96]. Simvastatin has also proven successful in reducing tumor growth in patient-derived xenograft mouse models [97]. However, statins are often associated with poor bioavailability as they are sparingly soluble in water and have low tissue permeability [98]. Simvastatin-loaded liposome nanoparticles were therefore developed in an attempt to increase the bioavailability of the drug [41]. Although the study was unsuccessful in this goal, alternative nanoparticle formulations optimized for uterine fibroid delivery could yield further treatment options for patients beyond surgery. Nanoparticles may also facilitate typical treatment courses for uterine fibroids. For example, SPIO nanoparticle-embedded chitosan microspheres have been investigated as a novel agent for uterine fibroid embolization. These microspheres demonstrated improved segmental arterial occlusion compared with the typically used polyvinyl alcohol particles in uterine arterial embolization of rabbits while also being traceable by MRI scanning [45]. Sexual health Sexually transmitted infections (STIs) are a significant issue worldwide. The UK reported record numbers of gonorrhea cases in 2022 and the highest number of cases of syphilis since 1948 [99]. Streamlining the process of STI detection through a sensitive and user-friendly point-of-care diagnostic method is one of the best methods of control, as these infections are often asymptomatic with the risk of developing severe complications when left untreated. Diagnosis A possible sensitive, low-cost method for the treatment of Neisseria gonorrhoeae was developed by Liu et al. in 2017 using loop-mediated isothermal amplification of an N. gonorrhoeae pseudogene [46]. This technique was then refined by the addition of a gold nanoparticle-based lateral flow biosensor. This biosensor provides a visual readout following the loop-mediated isothermal amplification reaction and requires more basic equipment than the current gold standard PCR testing methods [47]. This method also proved suitable for the identification of Chlamydia trachomatis. These methods have the potential to develop home-testing kits which could increase accessibility to testing facilities, thus facilitating the rapid diagnosis of STIs before they are transmitted to others. Prevention Despite the use of barrier methods to prevent the transmission of STIs, male condoms provide variable protection against transmission, ranging from >90% estimated efficacy against HIV and hepatitis B to 10–50% against HSV-2 [100]. Increasing the efficacy of STI prevention is important for the reproductive health of all people, regardless of gender, and improving the range of contraception methods available is especially beneficial for the sexual freedom of women. Polyurethane condoms coated with silver nanoparticles exhibit additional antimicrobial properties and were shown to successfully inactivate HSV-1, HSV-2 and HIV-1, but did not exhibit a toxic effect on three different cell lines (HeLa cells, 293 T cells and C8166 T cells) [51]. This could provide an additional line of defense against STIs. Natural rubber latex, when mixed with 30-nm silver nanoparticles, permitted the gradual release of these nanoparticles [101]. This provides another possible route for the development of nanoparticle-loaded condoms that could act both as a contraceptive and as a chemical and physical barrier to STI transmission [52]. Nanoparticles continue to be investigated by researchers by virtue of their antimicrobial properties [102] and may have other applications for the reduction of STIs or in improving contraceptives. Mucus-penetrating nanoparticles coated with PEG diffuse through cervicovaginal mucus at speeds near those of their diffusion through water, and can be loaded with acyclovir monophosphate and applied vaginally to improve protection against HSV-2 in a mouse model [58]; these mucus-penetrating particles could also be applied to the local delivery of other drugs for action in the cervicovaginal tract. Electrospun nanofibers may enhance the delivery of the HIV pre-exposure prophylactic drugs tenofovir disoproxil fumarate and emtricitabine in women, using a vaginal delivery route rather than oral administration. Both drugs were effectively released from the fibers in trials in mice, showing a higher concentration of drugs at the target than in mice treated with oral drug preparations [53]. Polymeric PLGA has been used as a pH-dependent capsule for tenofovir, which only releases its cargo when exposed to the increase in pH caused by the presence of semen [103]. Similarly, vaginal films have been developed to allow pH-dependent drug release [104], and with the addition of plasticizers PEG and oleic acid, these films have been shown to reduce systemic exposure while maintaining effective mucosal levels of tenofovir in mice [54]. Polymeric nanoparticles, in the form of gels, have been investigated to prevent the vaginal transmission of HIV while also acting as a contraceptive. These nanoparticles, made of poly(methacrylic acid-co-acrylates), are pH-responsive and dissolve to release their cargo of both an antiviral agent (atazanavir sulfate) and a spermicide (fluoxetine hydrochloride) when exposed to the higher pH of semen (pH 7.2), but will not release these drugs within the normal pH range of the vagina (pH 3.8–5) [105]. This potential dual-effect formulation showed no toxicity or irritancy in trials in experimental mice. Intrauterine devices often accumulate biofilms and may contaminate the endometrial cavity with bacteria when inserted [106]; this can lead to pelvic inflammatory disease. Many pathogenic bacteria have been identified on intrauterine devices following removal [107]. Coating intrauterine devices with antimicrobial nanoparticles, such as silver or zinc oxide [108], could help to reduce biofilm formation on intrauterine devices and thereby reduce associated inflammation. Vaccination Vaccination formulations may be improved by the integration of nanotechnology, thus providing an alternative form of protection from STIs. Estimates show that 67% of the global population could have HSV-1 infections, with a further 13% estimated to have HSV-2 infections [109]. Women are infected by HSV-2 twice as often as men, as sexual transmission is more efficient from men to women; therefore, the development of a suitable vaccine would offer additional protection. A trivalent mRNA vaccine has been developed that can be delivered to cells when encapsulated in a lipid nanoparticle [59]. The encased mRNA encodes three glycoproteins found in HSV: gD2, which is required for receptor engagement; gC, which can block activation of the complement system; and gE2, which interacts with gI2 to block antibody-dependent cellular toxicity. This vaccine was effective in trials in both mice and guinea pigs, inducing both T-follicular helper cell and memory B-cell responses. Exosomes have provided a possible platform for the production of therapeutic vaccines to treat human papillomavirus (HPV). HPV infections are alarmingly high, with an estimated 13 million new disease-associated HPV infections in the USA in 2018 [110]. Three different vaccine strategies were explored by Rezaei et al., including one in which exosomes were loaded with recombinant heat-shock protein 27 fused to HPV16 E7. This vaccine platform successfully induced cytokine and antibody responses in mouse models and also reduced tumor size when administered as a prophylactic [60]. The exosome platform for vaccination has great potential for further applications and should be a growing area of exploration, as exosomes can be further modified to aid immunogenicity. Nanotechnology has also provided potential nanovaccine formulations to combat gonorrhea. Helicobacter pylori ferritin has been investigated as a possible antigen-presenting platform to prime the immune system for an adaptive immune response [48]. It self-assembles into a cage of 24 identical subunits, between which N. gonorrhoeae MtrE loops can be added. This makes these antigenic peptides accessible to antibody binding when presented on the nanocage surface [49], thus rendering these functionalized nanocage structures an attractive candidate for further vaccine development. A similar approach has been taken in the development of a candidate HIV vaccine, in which different formulations of the envelope protein from HIV strains were attached to the N-termini of bacterial ferritin, thus presenting multiple possible antigens that help to prime the immune system to mount a response upon infection [55]. This study was successful in stimulating neutralizing antibody responses in guinea pigs and therefore provides a viable starting point for developing vaccines that can simultaneously protect against multiple strains of HIV. Other nanotechnology vaccines for HIV are also under development [56]. A recent study showed that nanoparticles are a suitable vehicle with which to introduce HIV-specific broadly neutralizing antibodies to humans via vaccination [57]. This self-assembling nanoparticle holds several advantages over recombinant subunit vaccines, including improved in vivo trafficking, stronger immunogenicity and the potential to present multimeric antigens. This vaccine induced vaccine-specific CD4+ T-cell production, with diverse phenotypes and functions. This provides another potential route for vaccination against HIV. An alternative approach to developing a gonorrhea vaccine with nanotechnology has also been investigated which utilizes whole-cell inactivated N. gonorrhoeae in microparticles. Whole-cell vaccines have the advantage of carrying multiple possible antigens against which the adaptive immune system can mount a response. This vaccine produced an antigen-specific antibody and T-cell responses in an in vivo vaccination study in mice [50], thus providing another possible route to successful vaccination. Rethinking in vitro fertilization/ART Infertility is a common event in many reproductive health conditions; therefore, ART is also a key concern in this area. Endometriosis alone is estimated to account for half of all infertile women, with up to 25% of all women with endometriosis requiring ART to conceive [111]. Infertility is a growing concern across the population, with one in six couples experiencing infertility over their lifetime according to the World Health Organization [112]. Infertility is defined as the failure to conceive following 1 year of unprotected sexual intercourse [112]. Infertility can be caused by female factors, male factors, a combination of male and female factors, or can be idiopathic. The birth of the first in vitro fertilization baby in 1978 [113] led to the rapid development of ART, a technology that can help to overcome infertility. At present, a complex suite of sophisticated laboratory techniques is available under the umbrella term of ART, with a capability that is outpacing both legal and ethical regulation. However, despite these developments, the success rates of ART remain at 25% live births per cycle, with the majority of ART cycles resulting in failure [114]. Nanoparticles may be able to facilitate some of these conventional ART techniques, while also providing us with efficient tools to investigate methods with which to improve success rates (Figure 4). Sperm loading Nanoparticles may provide a simple and efficient means of loading biological factors into sperm to augment fertility. For example, Makhluf et al. showed that magnetic nanoparticles could be loaded into sperm spontaneously without affecting their motility or their ability to fertilize an egg [115]; subsequently, the same group demonstrated that modified magnetite nanoparticles could act as protein carriers [116]. Sperm are not easy to penetrate; therefore, gaining the ability to load these specialized cells with supplementary biological factors could provide a route by which to load wild-type versions of defective proteins into sperm cells that are not fertilization competent, or to allow the addition of drug molecules to influence sperm activity. Mesoporous silica nanoparticles (MSNPs) may offer another safe delivery tool for the introduction of biological factors to sperm. Barkalina et al. showed that MSNPs loaded with nucleic acid or protein can successfully interact with boar sperm without compromising key parameters of sperm function such as viability, motility, acrosomal status and DNA fragmentation index (Figure 5) [117]. Furthermore, MSNPs can be functionalized with a specific cell-penetrating peptide (C105Y) to increase their binding affinity toward gametes without negatively affecting sperm function, instead associating with the head and midpiece and acting as a protective factor for acrosome morphology and duration of motility [118]. These developments may help to overcome issues of low efficacy in the internalization of compounds into gametes, thereby improving techniques that depend on intragamete delivery. Gamete & embryo preservation Not all sperm survive cryopreservation; this is due to the oxidative stress caused by the freezing and thawing processes [119]. Cerium oxide nanoparticles, as trialed for their use as ROS scavengers in endometriosis, may also help to improve the survival and fertilization capabilities of frozen/thawed sperm cells [120]. In this study, CeO2 nanoparticles were shown to improve motility and membrane integrity, but without inducing an effect on ROS levels; the mechanisms underlying these beneficial effects have yet to be elucidated [120]. Cryopreserving human sperm with exosomes from seminal fluid showed an increase in sperm viability, motility and morphology as well as a reduction in ROS levels and DNA damage, suggesting that they can play a cryoprotective role [121]. The oxidative stress associated with cryopreservation can lead to reduced plasma membrane integrity, as evidenced by alterations in protein–lipid interactions and a reduction in the amount of cholesterol in cell membranes [122]. This could lead to premature acrosome reactions in thawed sperm, thus leading to fertilization failure. Membrane lipid replacement with nanomicelles has been posed as a possible solution to this issue [123]. The incorporation of cholesterol-loaded cyclodextrin prior to cryopreservation has been shown to improve the quality of frozen/thawed sperm from a range of different species [124]. Furthermore, the incubation of human sperm with micelles of glycerophospholipid mixtures was shown to increase both motility and resistance to oxidative stress [125]. The application of micelles that carried both cholesterol-loaded cyclodextrin and glycerophospholipids resulted in increased motility, mitochondrial activity and acrosome integrity in frozen/thawed human sperm when compared with thawed but untreated sperm [123]. Low-density lipoprotein nanoparticles produced by the probe ultrasonification of egg yolk plasma may also offer cryoprotection for frozen sperm samples, as demonstrated in semen from the canine model. These nanoparticles have a high-reactivity surface and help preserve membrane integrity during the biological stress associated with freezing and thawing [126]. In ART, oocytes are often vitrified in order to preserve fertility in women who are likely to experience a loss in fertility, such as those who require gonadotoxic treatments. Fe3O4 nanoparticles have demonstrated potential as vitrification aids, as evidenced by a significant increase in the nuclear maturity of oocytes that were incubated with these nanoparticles prior to vitrification [127]. The lowest concentration of Fe3O4 nanoparticles tested was associated with the highest viability; this may be due to the nanoparticles’ ability to generate destructive free radicals. Follicular fluid exosomes, while they do not affect the viability of thawed oocytes, have also been shown to increase the meiotic competence of domestic cat oocytes when added to either vitrification or thawing media; proteins that regulate tight junction and gap junction formation were present in the cat follicular fluid exosomes, which may have aided in maintaining intercellular signaling post-vitrification [128]. Silica nanoparticles may facilitate the in vitro maturation of oocytes, as demonstrated in the domestic pig. The addition of highly dispersed silica nanoparticles was found to reduce apoptosis and increase embryo yield, thus suggesting that these nanoparticles would be a useful addition to culture media designed for the extracorporeal maturation of oocytes; this strategy could improve the quality of the collected eggs and their chances of successful fertilization [129]. Nanoparticles could also help to improve the rates of cryopreservation and thawing of embryos produced by ART, which are typically considered as limiting factors in the improvement of embryo cryopreservation. Laser-assisted gold nanoparticle warming, in which gold nanorods are injected through the embryo to increase thermal conductivity, has been shown to improve the survival of zebrafish embryos following cryopreservation [130,131]; this effect has been elusive for many years due to slow convective heating through the large mass of embryos. Thermally conductive graphene-based nanofluids may also maximize heating and cooling rates that are otherwise limited by the heat conductivity of the aqueous media of embryos. A trial that utilized mouse blastocysts showed that a graphene oxide nanoparticle cryosolution was as effective as a typical sucrose solution in terms of hatching and implantation rates, but also allowed embryos to maintain their spherical shape throughout dehydration [132]. This technique caused less thermal and physical stress on embryos and did not compromise their viability. Preterm birth Nanoparticles may also aid women throughout pregnancy, increasing the likelihood of carrying a baby to term. The use of nanoparticles in pregnancy carries additional risks, as genetic or epigenetic changes to the fetus caused by nanoparticles in utero may be inherited, causing cross-generational detrimental effects. Globally, an estimated 11.1% of all livebirths in 2010 were born preterm (prior to 37 weeks of gestation), and this figure has remained constant for the last few decades [133]. Preterm birth can be caused by a variety of medical, psychosocial and biological factors. Preterm birth is estimated to be a risk factor in over 50% of all neonatal deaths and can lead to long-term complications in survivors [134]. Despite this, only one drug has been approved for the prevention of preterm birth by the US FDA until its withdrawal in April 2023 [135]. Nanoparticles are an attractive prospect for medications during pregnancy as they can travel through the cervicovaginal mucous barrier and reach target tissues with lower systemic drug levels and further reduce placental barrier penetration [136]. Two different preclinical studies have shown that a self-nanoemulsifying drug-delivery system can delay the onset of inflammation-induced preterm births; one study showed that the combination of such a system with a sphingosine kinase inhibitor II drug cargo increased the number of mouse pups rescued from preterm birth in lipopolysaccharide-induced pups [137], while the other tested a similar vaginal formulation with 17-α-hydroxyprogesterone caproate as the cargo with a similar significant increase in the number of rescued pups [138]. Another nanosuspension containing progesterone encapsulated in PEGylated nanoparticles showed significant prevention of preterm birth, performing better than the gel equivalent, in a mouse model of progesterone withdrawal [139]. In addition, a vaginal nanoformulation carrying trichostatin A (a histone deacetylase inhibitor) and progesterone led to a reduction in inflammation-induced preterm birth by 50% in a mouse model [140]. These vaginal nanoformulations have the potential to reduce the number of preterm births and protect both the mother and the newborn from the possible risks associated with preterm birth. Concerns relating to the use of nanoparticles Although nanoparticles provide us with a range of different methods to improve our ability to enhance the reproductive health of women and our ability to provide ART, there are several concerns related to their application, ranging from safety to environmental issues. An estimated 20% of clinical trials involving nanoparticles fail due to safety concerns [141], clearly showing that this area requires further investigation. The toxicity of nanoparticles must be carefully investigated before their widespread introduction in clinical scenarios, and this is an active area of current research [142]. A wide range of nanotoxicities have been reported, from gold nanorods aggravating immune-mediated hepatitis in mice [143] to abnormal offspring from maternal mice injected with reduced graphene oxide nanosheets [144]; gold nanorods have been investigated as a potential improved MRI contrast agent [21]. Nanoparticles can cross the blood–brain barrier; while this is a benefit in some scenarios, it can also pose significant risks [145]. Nanoparticles can induce oxidative stress, including silver nanoparticles which are widely used as an antibacterial nanomaterial [146,147]. Oxidative stress has been confirmed in the brains of rats following the inhalation of MnO2 nanoparticles [148]. Oxidative stress in the brain has been implicated in the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [149]. However, silver nanoparticles have been investigated for a range of applications, including an oral PCOS treatment which may have systemic effects as a result, which was not included in the mouse-model study [8]. The potential ability of nanoparticles for clinical applications to penetrate the nervous system must be carefully assessed prior to clinical translation. Nanoparticles have also been implicated in reproductive and developmental nanotoxicity, with concerns over potential embryo/fetal toxicity due to their ability to cross biological barriers such as the blood–brain barrier, blood–testis barrier and placenta [150]. Higher concentrations of titanium nanoparticles in the maternal blood are associated with a greater risk of congenital heart defects [151]. In the testes, both carbon and silver nanoparticles are known to negatively affect both Leydig and Sertoli cells by inducing oxidative stress and reducing mitochondrial membrane potential; these cell types are crucial for successful spermatogenesis [152,153], so this effect may warrant further investigation before the use of silver nanoparticle-coated condoms to prevent STI transmission [52,101]. There is also evidence that the accumulation of nanoparticles may lead to abnormalities in sperm production [154]. For example, titanium dioxide and zinc oxide nanoparticles have been linked to genotoxicity in human sperm cells by causing an increase in ROS [155]. Zinc oxide nanoparticles have also been shown to enhance apoptosis in Leydig cells, thus leading to reduced testosterone levels and impaired spermatogenesis [156]. Titanium dioxide nanoparticles have also been shown to cause a significant reduction in the number of eggs produced by female zebrafish following 13 weeks of exposure [157]. Furthermore, zinc oxide nanoparticles reduce fertility by inducing cytotoxicity and by promoting oxidative stress, autophagy and apoptosis in developing zebrafish oocytes [158]. These nanoparticle types have been primarily explored for use in ART, so long-term effects on the fetus must be carefully studied. Nanoparticles may even pose a barrier to ART; even very low levels of cerium oxide in a culture medium during in vitro fertilization resulted in a reduction in fertilization rate in mouse models [159]. Although extracellular vesicles do not face the same challenges as synthetic nanoparticles in terms of tolerance and toxicity, there are challenges in developing the required technology for their clinical use. Exosomes are complex and there is much more variability introduced through biogenesis than synthetic manufacture, posing challenges for reproducibility and reliability [160]. Additionally, methods to purify exosomes and the demands of cell culture limit scaling up production for clinical applications. There are also concerns that exosomes may be rapidly degraded in the body; however, a study in 2003 showed that antigen-presenting cell exosomes express CD55 and CD59, which protects them from lysis by the complement system [161]. Further explorations into exosome modification to optimize bioavailability and reduce variability are required before they can be applied reliably.

Advancements in nanotechnology provide a range of new possibilities for the diagnosis, treatment and prevention of many conditions, including diseases of the female reproductive system, while also offering potential new avenues for ART. Nanoparticles can be well adapted in order to face the challenges of delivery to the female reproductive organs and gamete penetration. Many of the possibilities discussed are directly associated with the ability of both lipid- and metal-derived nanoparticles to increase delivery efficacy and accuracy of active pharmaceutical ingredients, along with their potential to reduce drug-taking noncompliance through sustained-release delivery systems. Other new possibilities are related to their intrinsic properties as biologically active particles, especially metal-derived nanoparticles, though these require significant further investigation. Nanoparticles also provide an exciting platform for the development of vaccines for STIs, which could help reduce the growing number of STIs diagnosed each year. Overall, nanoparticles have many exciting potential applications and represent an important route for further investigation into improving outcomes in women’s reproductive health and ART. Future perspective With so many potential benefits for patients, it is vital that researchers increase their focus on preclinical testing in order to translate these findings safely into the clinic. Several factors still require further consideration before nanoparticles can become accessible in a clinical context for reproductive health. Questions remain over the cytotoxicity of nanoparticles and also over the potential effects of their bioaccumulation, which is a particular issue for synthetic and metal nanoparticles. Further research into the safety and application is paramount, especially given that the potential benefits of nanoparticles in a clinical setting cannot be understated. Methods that can localize nanoparticles to reduce systemic risks may be of key importance to the field as it develops. The use of extracellular vesicles as drug-delivery vehicles is an exciting prospect for further research, as they are already found and tolerated in the body, while further toxicity and tolerance testing on metal-based nanoparticles is required before their translation into clinical studies and into the clinic. Nanoparticle research provides a valuable and exciting new direction for research into women’s reproductive health conditions and ART which will bring new approaches to improve outcomes. Supplementary Material Financial disclosure The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Competing interests disclosure The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Writing disclosure No writing assistance was utilized in the production of this manuscript.

Papers of special note have been highlighted as: • of interest; •• of considerable interest - 1.Anselmo AC, Mitragotri S. Nanoparticles in the clinic: an update. Bioeng. Transl. Med. 4(3), e10143 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 2.Garbayo E, Pascual-Gil S, Rodriguez-Nogales C, Saludas L, Estella-Hermoso De Mendoza A, Blanco-Prieto MJ. Nanomedicine and drug delivery systems in cancer and regenerative medicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 12(5), e1637 (2020). [DOI] [PubMed] [Google Scholar] - 3.Pei Z, Chen S, Ding Let al. Current perspectives and trend of nanomedicine in cancer: a review and bibliometric analysis. J. Control. Rel. 352, 211–241 (2022). [DOI] [PubMed] [Google Scholar] - 4.Roth LQ, McCallie B, Alvero R, Schoolcraft WB, Minjarez D, Katz-Jaffe MG. Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome. J. Assist. Reprod. Genet. 31(3), 355–362 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar] - 5.Hu J, Tang T, Zeng Z, Wu J, Tan X, Yan J. The expression of small RNAs in exosomes of follicular fluid altered in human polycystic ovarian syndrome. PeerJ 8, e8640 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 6.Li J, Li Y, Li Pet al. Exosome detection via surface-enhanced Raman spectroscopy for cancer diagnosis. Acta Biomater. 144, 1–14 (2022). [DOI] [PubMed] [Google Scholar] - 7.Rabah HM, Mohamed DA, Mariah RAet al. Novel insights into the synergistic effects of selenium nanoparticles and metformin treatment of letrozole-induced polycystic ovarian syndrome: targeting PI3K/Akt signalling pathway, redox status and mitochondrial dysfunction in ovarian tissue. Redox Rep. 28(1), 2160569 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar] - 8.Alwan SH, Al-Saeed MH. Silver nanoparticles biofabricated from Cinnamomum zeylanicum reduce IL-6, IL-18, and TNF-ɑ in female rats with polycystic ovarian syndrome. Int. J. Fertil. Steril. 17(1), 80–84 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar] - 9.Xie Q, Xiong X, Xiao Net al. Mesenchymal stem cells alleviate DHEA-induced polycystic ovary syndrome (PCOS) by inhibiting inflammation in mice. Stem Cells Int. 2019, 9782373 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 10.Zhao Y, Tao M, Wei M, Du S, Wang H, Wang X. Mesenchymal stem cells derived exosomal miR-323-3p promotes proliferation and inhibits apoptosis of cumulus cells in polycystic ovary syndrome (PCOS). Artif. Cells Nanomed. Biotechnol. 47(1), 3804–3813 (2019). [DOI] [PubMed] [Google Scholar] - 11.Zhao Y, Pan S, Wu X. Human umbilical cord mesenchymal stem-cell derived exosomes inhibit ovarian granulosa cells inflammatory response through inhibition of NF-κB signalling in polycystic ovary syndrome. J. Reprod. Immunol. 152, 103638 (2022). [DOI] [PubMed] [Google Scholar] - 12.Raja MA, Maldonado M, Chen J, Zhong Y, Gu J. Development and evaluation of curcumin encapsulated self-assembled nanoparticles as potential remedial treatment for PCOS in a female rat model. Int. J. Nanomed. 16, 6231–6247 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 13.Fatemi Abhari SM, Khanbabaei R, Hayati Roodbari N, Parivar K, Yaghmaei P. Curcumin-loaded super-paramagnetic iron oxide nanoparticle affects on apoptotic factors expression and histological changes in a prepubertal mouse model of polycystic ovary syndrome-induced by dehydroepiandrosterone – a molecular and stereological study. Life Sci. 249, 117515 (2020). [DOI] [PubMed] [Google Scholar] - 14.Salem HF, Kharshoum RM, Abou-Taleb HA, Aboutaleb HA, Abouelhassan KM. Progesterone-loaded nanosized transethosomes for vaginal permeation enhancement: formulation, statistical optimization, and clinical evaluation in anovulatory polycystic ovary syndrome. J. Liposome Res. 29(2), 183–194 (2019). [DOI] [PubMed] [Google Scholar] - 15.Butt MA, Shafique HM, Mustafa Met al. Therapeutic potential of selenium nanoparticles on letrozole-induced polycystic ovarian syndrome in female Wistar rats. Biol. Trace Elem. Res. 201(11), 5213–5229 (2023). [DOI] [PubMed] [Google Scholar] - 16.Park HS, Cetin E, Siblini Het al. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles to treat PCOS. Int. J. Mol. Sci. 24(13), 11151 (2023). doi: 10.3390/ijms241311151 [DOI] [PMC free article] [PubMed] [Google Scholar] - 17.Cao M, Zhao Y, Chen Tet al. Adipose mesenchymal stem cell-derived exosomal microRNAs ameliorate polycystic ovary syndrome by protecting against metabolic disturbances. Biomaterials 288, 121739 (2022). [DOI] [PubMed] [Google Scholar] - 18.Khalaj K, Miller JE, Lingegowda Het al. Extracellular vesicles from endometriosis patients are characterized by a unique miRNA–lncRNA signature. JCI Insight 4(18), doi: 10.1172/jci.insight.128846 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 19.Lee HJ, Lee HJ, Lee JM, Chang Y, Woo ST. Ultrasmall superparamagnetic iron oxides enhanced MR imaging in rats with experimentally induced endometriosis. Magn. Reson. Imaging 30(6), 860–868 (2012). [DOI] [PubMed] [Google Scholar] - 20.Zhang H, Li J, Sun Wet al. Hyaluronic acid-modified magnetic iron oxide nanoparticles for MR imaging of surgically induced endometriosis model in rats. PLOS ONE 9(4), e94718 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar] - 21.Marquardt RM, Nafiujjaman M, Kim THet al. A mouse model of endometriosis with nanoparticle labeling for in vivo photoacoustic imaging. Reprod. Sci. 29(10), 2947–2959 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 22.Sangili A, Kalyani T, Chen SM, Nanda A, Jana SK. Label-free electrochemical immunosensor based on one-step electrochemical deposition of AuNP-RGO nanocomposites for detection of endometriosis marker CA 125. ACS Appl. Bio Mater. 3(11), 7620–7630 (2020). [DOI] [PubMed] [Google Scholar] - 23.Kalyani T, Sangili A, Nanda A, Prakash S, Kaushik A, Kumar Jana S. Bio-nanocomposite based highly sensitive and label-free electrochemical immunosensor for endometriosis diagnostics application. Bioelectrochemistry 139, 107740 (2021). [DOI] [PubMed] [Google Scholar] - 24.Yuan M, Ding S, Meng Tet al. Effect of A-317491 delivered by glycolipid-like polymer micelles on endometriosis pain. Int. J. Nanomed. 12, 8171–8183 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar] - 25.Zhao MD, Cheng JL, Yan JJet al. Hyaluronic acid reagent functional chitosan–PEI conjugate with AQP2-siRNA suppressed endometriotic lesion formation. Int. J. Nanomed. 11, 1323–1336 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar] - 26.Zhao MD, Sun YM, Fu GFet al. Gene therapy of endometriosis introduced by polymeric micelles with glycolipid-like structure. Biomaterials 33(2), 634–643 (2012). [DOI] [PubMed] [Google Scholar] - 27.Chaichian S, Mehdizadeh Kashi A, Tehermanesh K, Pirhajati Mahabadi V, Minaeian S, Eslahi N. Effect of PLGA nanoparticle-mediated delivery of miRNA 503 on the apoptosis of ovarian endometriosis cells. Cell J. 24(11), 697–704 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 28.Davoodi Asl F, Sahraei SS, Kalhor Net al. Promising effects of exosomes from menstrual blood-derived mesenchymal stem cells on endometriosis. Reprod. Biol. 23(3), 100788 (2023). [DOI] [PubMed] [Google Scholar] - 29.Wu D, Lu P, Mi X, Miao J. Exosomal miR-214 from endometrial stromal cells inhibits endometriosis fibrosis. Mol. Hum. Reprod. 24(7), 357–365 (2018). [DOI] [PubMed] [Google Scholar] - 30.Chaudhury K, Babu KN, Singh AK, Das S, Kumar A, Seal S. Mitigation of endometriosis using regenerative cerium oxide nanoparticles. Nanomedicine 9(3), 439–448 (2013). [DOI] [PubMed] [Google Scholar] - 31.Sun Q, Lei Y, Zhang Het al. A multifunctional nanoparticle for efferocytosis and pro-resolving-mediated endometriosis therapy. Colloids Surf. B Biointerfaces 220, 112893 (2022). [DOI] [PubMed] [Google Scholar] - 32.Bedin A, Maranhao RC, Tavares ER, Carvalho PO, Baracat EC, Podgaec S. Nanotechnology for the treatment of deep endometriosis: uptake of lipid core nanoparticles by LDL receptors in endometriotic foci. Clinics (Sao Paulo) 74, e989 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 33.De Almeida Borges VR, Da Silva JH, Barbosa SS, Nasciutti LE, Cabral LM, De Sousa VP. Development and pharmacological evaluation of in vitro nanocarriers composed of lamellar silicates containing copaiba oil-resin for treatment of endometriosis. Mater. Sci. Eng. C Mater. Biol. Appl. 64, 310–317 (2016). [DOI] [PubMed] [Google Scholar] - 34.Liu Q, Ma P, Liu Let al. Evaluation of PLGA containing anti-CTLA4 inhibited endometriosis progression by regulating CD4+CD25+Treg cells in peritoneal fluid of mouse endometriosis model. Eur. J. Pharm. Sci. 96, 542–550 (2017). [DOI] [PubMed] [Google Scholar] - 35.Boroumand S, Hosseini S, Pashandi Z, Faridi-Majidi R, Salehi M. Curcumin-loaded nanofibers for targeting endometriosis in the peritoneum of a mouse model. J. Mater. Sci. Mater. Med. 31(1), 8 (2019). [DOI] [PubMed] [Google Scholar] - 36.Sun XZ, Williams GR, Hou XX, Zhu LM. Electrospun curcumin-loaded fibers with potential biomedical applications. Carbohydr. Polym. 94(1), 147–153 (2013). [DOI] [PubMed] [Google Scholar] - 37.Moses AS, Taratula OR, Lee Het al. Nanoparticle-based platform for activatable fluorescence imaging and photothermal ablation of endometriosis. Small 16(18), e1906936 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 38.Park Y, Demessie AA, Luo Aet al. Targeted nanoparticles with high heating efficiency for the treatment of endometriosis with systemically delivered magnetic hyperthermia. Small 18(24), e2107808 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]; •• Provides a new possibility for targeted treatment of endometriosis that does not require surgery: magnetic nanoparticles introduced systemically are delivered to endometriotic lesions and effectively heated to lethal temperatures, with a remarkably targeted effect. There is still a need for significant development before this is clinically viable. - 39.Ali H, Kilic G, Vincent K, Motamedi M, Rytting E. Nanomedicine for uterine leiomyoma therapy. Ther. Deliv. 4(2), 161–175 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar] - 40.Enazy SA, Kirschen GW, Vincent Ket al. PEGylated polymeric nanoparticles loaded with 2-methoxyestradiol for the treatment of uterine leiomyoma in a patient-derived xenograft mouse model. J. Pharm. Sci. 112(9), 2552–2560 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar] - 41.El Sabeh M, Vincent KL, Afrin Set al. Simvastatin-loaded liposome nanoparticles treatment for uterine leiomyoma in a patient-derived xenograft mouse model: a pilot study. J. Obstet. Gynaecol. 42(6), 2139–2143 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 42.Shalaby SM, Khater MK, Perucho AMet al. Magnetic nanoparticles as a new approach to improve the efficacy of gene therapy against differentiated human uterine fibroid cells and tumor-initiating stem cells. Fertil. Steril. 105(6), 1638–1648; e1638 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar] - 43.Egorova A, Selutin A, Maretina M, Selkov S, Kiselev A. Peptide-based nanoparticles for alphavbeta3 integrin-targeted DNA delivery to cancer and uterine leiomyoma cells. Molecules 27(23), doi: 10.3390/molecules27238363 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 44.Shtykalova S, Egorova A, Maretina M, Baranov V, Kiselev A. Magnetic nanoparticles as a component of peptide-based DNA delivery system for suicide gene therapy of uterine leiomyoma. Bioengineering (Basel) 9(3), doi: 10.3390/bioengineering9030112 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]; • Presents a new possibility for nonsurgical treatment of uterine fibroids, using nanoparticles to improve the delivery and transfection efficiency of nonviral carriers for suicide gene delivery, helping to overcome issues of lesion density that make gene delivery challenging for this condition. - 45.Choi SY, Kwak BK, Shim HJ, Lee J, Hong SU, Kim KA. MRI traceability of superparamagnetic iron oxide nanoparticle-embedded chitosan microspheres as an embolic material in rabbit uterus. Diagn. Interv. Radiol. 21(1), 47–53 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar] - 46.Liu ML, Xia Y, Wu XZ, Huang JQ, Guo XG. Loop-mediated isothermal amplification of Neisseria gonorrhoeae porA pseudogene: a rapid and reliable method to detect gonorrhea. AMB Express 7(1), 48 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar] - 47.Chen X, Zhou Q, Yuan W, Shi Y, Dong S, Luo X. Visual and rapid identification of Chlamydia trachomatis and Neisseria gonorrhoeae using multiplex loop-mediated isothermal amplification and a gold nanoparticle-based lateral flow biosensor. Front. Cell. Infect. Microbiol. 13, 1067554 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]; • A new, sensitive, affordable and specific biosensor for chlamydia and gonorrhoea using nanoparticles may make diagnosis far more accessible. The gold nanoparticle-based lateral flow biosensor could also be applied to the diagnosis of other biomarkers for other conditions. - 48.Rodrigues MQ, Alves PM, Roldao A. Functionalizing ferritin nanoparticles for vaccine development. Pharmaceutics 13(10), doi: 10.3390/pharmaceutics13101621 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 49.Wang L, Xing D, Le Van A, Jerse AE, Wang S. Structure-based design of ferritin nanoparticle immunogens displaying antigenic loops of Neisseria gonorrhoeae. FEBS Open Bio. 7(8), 1196–1207 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar] - 50.Gala RP, Zaman RU, D’Souza MJ, Zughaier SM. Novel whole-cell inactivated Neisseria gonorrhoeae microparticles as vaccine formulation in microneedle-based transdermal immunization. Vaccines (Basel) 6(3), doi: 10.3390/vaccines6030060 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar] - 51.Mohammed Fayaz A, Ao Z, Girilal Met al. Inactivation of microbial infectiousness by silver nanoparticles-coated condom: a new approach to inhibit HIV- and HSV-transmitted infection. Int. J. Nanomed. 7, 5007–5018 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar] - 52.Yah CS, Simate GS, Hlangothi P, Somai BM. Nanotechnology and the future of condoms in the prevention of sexually transmitted infections. Ann. Afr. Med. 17(2), 49–57 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar] - 53.Nunes R, Bogas S, Faria MJet al. Electrospun fibers for vaginal administration of tenofovir disoproxil fumarate and emtricitabine in the context of topical pre-exposure prophylaxis. J. Control. Rel. 334, 453–462 (2021). [DOI] [PubMed] [Google Scholar] - 54.Notario-Perez F, Cazorla-Luna R, Martin-Illana Aet al. Influence of plasticizers on the pH-dependent drug release and cellular interactions of hydroxypropyl methylcellulose/zein vaginal anti-HIV films containing tenofovir. Biomacromolecules 22(2), 938–948 (2021). [DOI] [PubMed] [Google Scholar] - 55.Murji AA, Qin JS, Hermanus T, Morris L, Georgiev IS. Elicitation of neutralizing antibody responses to HIV-1 immunization with nanoparticle vaccine platforms. Viruses 13(7), doi: 10.3390/v13071296 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 56.Li S, Zhang MY, Yuan J, Zhang YX. Nano-vaccines for gene delivery against HIV-1 infection. Expert Rev. Vaccines 22(1), 315–326 (2023). [DOI] [PubMed] [Google Scholar] - 57.Cohen KW, De Rosa SC, Fulp WJet al. A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Sci. Transl. Med. 15(697), eadf3309 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]; • A possible HIV-1 vaccine has been an aim for many years, and this paper describes a vaccine that induced T-cell responses in humans, which may improve vaccine efficacy. - 58.Ensign LM, Tang BC, Wang YYet al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci. Transl. Med. 4(138), 138ra179 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar] - 59.Awasthi S, Friedman HM. An mRNA vaccine to prevent genital herpes. Transl. Res. 242, 56–65 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 60.Rezaei F, Bolhassani A, Sadat SMet al. Development of novel HPV therapeutic vaccine constructs based on engineered exosomes and tumor cell lysates. Life Sci. 340, 122456 (2024). [DOI] [PubMed] [Google Scholar] - 61.Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. Appl. Clin. Genet. 12, 249–260 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 62.Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum. Reprod. Update 20(5), 748–758 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar] - 63.Hoeger KM, Dokras A, Piltonen T. Update on PCOS: consequences, challenges, and guiding treatment. J. Clin. Endocrinol. Metab. 106(3), e1071–e1083 (2021). [DOI] [PubMed] [Google Scholar] - 64.Javid-Naderi MJ, Mahmoudi A, Kesharwani P, Jamialahmadi T, Sahebkar A. Recent advances of nanotechnology in the treatment and diagnosis of polycystic ovary syndrome. J. Drug Deliv. Sci. Technol. 79, 104014 (2023). [Google Scholar] - 65.Nasimi P, Haidari M. Medical use of nanoparticles: drug delivery and diagnosis diseases. Int. J. Green Nanotechnol. 1, 1943089213506978 (2013). [Google Scholar] - 66.Musielak E, Feliczak-Guzik A, Nowak I. Synthesis and potential applications of lipid nanoparticles in medicine. Materials (Basel) 15(2), doi: 10.3390/ma15020682 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 67.Kalluri R, Lebleu VS. The biology, function and biomedical applications of exosomes. Science 367(6478), doi: 10.1126/science.aau6977 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 68.Li T, Mo H, Chen Wet al. Role of the PI3K-Akt signaling pathway in the pathogenesis of polycystic ovary syndrome. Reprod. Sci. 24(5), 646–655 (2017). [DOI] [PubMed] [Google Scholar] - 69.Abdallah ABE, El-Ghannam MA, Hasan AA, Mohammad LG, Mesalam NM, Alsayed RM. Selenium nanoparticles modulate steroidogenesis-related genes and improve ovarian functions via regulating androgen receptors expression in polycystic ovary syndrome rat model. Biol. Trace Elem. Res. 201(12), 5721–5733 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]; • Selenium nanoparticles tested in a rat model were effective at treating the metabolic, endocrine and reproductive symptoms of polycystic ovary syndrome. This paper shows how steroidogenesis is altered by selenium nanoparticles, reducing hyperandrogenism in young adult rats with induced polycystic ovary syndrome. - 70.Gao L, Gu Y, Yin X. High serum tumor necrosis factor-alpha levels in women with polycystic ovary syndrome: a meta-analysis. PLOS ONE 11(10), e0164021 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar] - 71.Fulghesu AM, Sanna F, Uda S, Magnini R, Portoghese E, Batetta B. IL-6 serum levels and production is related to an altered immune response in polycystic ovary syndrome girls with insulin resistance. Mediators Inflamm. 2011, 389317 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar] - 72.Liao Z, Liu C, Wang L, Sui C, Zhang H. Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in female reproductive diseases. Front. Endocrinol. (Lausanne) 12, 665645 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 73.Li YJ, Wu JY, Liu Jet al. Artificial exosomes for translational nanomedicine. J. Nanobiotechnol. 19(1), 242 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 74.Ellis K, Munro D, Clarke J. Endometriosis is undervalued: a call to action. Front. Glob. Womens Health 3, 902371 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 75.Tapmeier TT, Nazri HM, Subramaniam KSet al. Protocol for a longitudinal, prospective cohort study investigating the biology of uterine fibroids and endometriosis, and patients’ quality of life: the FENOX study. BMJ Open 10(3), e032220 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 76.Volpini C, Bloise N, Dominoni Met al. The nano-revolution in the diagnosis and treatment of endometriosis. Nanoscale 15(43), 17313–17325 (2023). [DOI] [PubMed] [Google Scholar] - 77.Scheck S, Paterson ESJ, Henry CE. A promising future for endometriosis diagnosis and therapy: extracellular vesicles – a systematic review. Reprod. Biol. Endocrinol. 20(1), 174 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 78.Bazot M, Darai E, Hourani Ret al. Deep pelvic endometriosis: MR imaging for diagnosis and prediction of extension of disease. Radiology 232(2), 379–389 (2004). [DOI] [PubMed] [Google Scholar] - 79.Grummer R. Animal models in endometriosis research. Hum. Reprod. Update 12(5), 641–649 (2006). [DOI] [PubMed] [Google Scholar] - 80.Sun IC, Ahn CH, Kim K, Emelianov S. Photoacoustic imaging of cancer cells with glycol-chitosan-coated gold nanoparticles as contrast agents. J. Biomed. Opt. 24(12), 1–5 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 81.Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat. Rev. Endocrinol. 10(5), 261–275 (2014). [DOI] [PubMed] [Google Scholar] - 82.Saraswat L, Ayansina D, Cooper KG, Bhattacharya S, Horne AW, Bhattacharya S. Impact of endometriosis on risk of further gynaecological surgery and cancer: a national cohort study. BJOG 125(1), 64–72 (2018). [DOI] [PubMed] [Google Scholar] - 83.Horne AW, Saunders PTK, Abokhrais IM, Hogg L, Endometriosis Priority Setting Partnership Steering Group . Top ten endometriosis research priorities in the UK and Ireland. Lancet 389(10085), 2191–2192 (2017). [DOI] [PubMed] [Google Scholar] - 84.Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil. Steril. 92(1), 68–74 (2009). [DOI] [PubMed] [Google Scholar] - 85.Saranya N, Moorthi A, Saravanan S, Devi MP, Selvamurugan N. Chitosan and its derivatives for gene delivery. Int. J. Biol. Macromol. 48(2), 234–238 (2011). [DOI] [PubMed] [Google Scholar] - 86.Zou LB, Zhang RJ, Tan YJet al. Identification of estrogen response element in the aquaporin-2 gene that mediates estrogen-induced cell migration and invasion in human endometrial carcinoma. J. Clin. Endocrinol. Metab. 96(9), E1399–E1408 (2011). [DOI] [PubMed] [Google Scholar] - 87.Gibran L, Maranhao RC, Tavares ER, Carvalho PO, Abrao MS, Podgaec S. mRNA levels of low-density lipoprotein receptors are overexpressed in the foci of deep bowel endometriosis. Hum. Reprod. 32(2), 332–339 (2017). [DOI] [PubMed] [Google Scholar] - 88.Ling C, Wang X, Shen Y. Advances in hollow inorganic nanomedicines for photothermal-based therapies. Int. J. Nanomed. 16, 493–513 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 89.Zhu S, Zhang J, Xue Net al. Highly specific neutrophil-mediated delivery of albumin nanoparticles to ectopic lesion for endometriosis therapy. J. Nanobiotechnol. 21(1), 81 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar] - 90.Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am. J. Obstet. Gynecol. 188(1), 100–107 (2003). [DOI] [PubMed] [Google Scholar] - 91.Shavell VI, Thakur M, Sawant Aet al. Adverse obstetric outcomes associated with sonographically identified large uterine fibroids. Fertil. Steril. 97(1), 107–110 (2012). [DOI] [PubMed] [Google Scholar] - 92.Moroni R, Vieira C, Ferriani R, Candido-Dos-Reis F, Brito L. Pharmacological treatment of uterine fibroids. Ann. Med. Health Sci. Res. 4(Suppl. 3), S185–S192 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar] - 93.Islam MS, Ciavattini A, Petraglia F, Castellucci M, Ciarmela P. Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics. Hum. Reprod. Update 24(1), 59–85 (2018). [DOI] [PubMed] [Google Scholar] - 94.Salama SA, Nasr AB, Dubey RK, Al-Hendy A. Estrogen metabolite 2-methoxyestradiol induces apoptosis and inhibits cell proliferation and collagen production in rat and human leiomyoma cells: a potential medicinal treatment for uterine fibroids. J. Soc. Gynecol. Investig. 13(8), 542–550 (2006). [DOI] [PubMed] [Google Scholar] - 95.Dahut WL, Lakhani NJ, Gulley JLet al. Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors. Cancer Biol. Ther. 5(1), 22–27 (2006). [DOI] [PubMed] [Google Scholar] - 96.Borahay MA, Kilic GS, Yallampalli Cet al. Simvastatin potently induces calcium-dependent apoptosis of human leiomyoma cells. J. Biol. Chem. 289(51), 35075–35086 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar] - 97.Borahay MA, Vincent K, Motamedi Met al. Novel effects of simvastatin on uterine fibroid tumors: in vitro and patient-derived xenograft mouse model study. Am. J. Obstet. Gynecol. 213(2), 196; e191–e198 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar] - 98.Petyaev IM. Improvement of hepatic bioavailability as a new step for the future of statin. Arch. Med. Sci. 11(2), 406–410 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar] - 99.UK Health Security Agency . Gonorrhoea and syphilis at record levels in 2022 (2023). www.gov.uk/government/news/gonorrhoea-and-syphilis-at-record-levels-in-2022 - 100.Mafartia YS, Pandya I, Mehta K. Condoms: past, present, and future. Indian J. Sex. Transm. Dis. AIDS 36(2), 133–139 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar] - 101.Guidelli ÉJ, Kinoshita A, Ramos AP, Baffa O. Silver nanoparticles delivery system based on natural rubber latex membranes. J. Nanopart. Res. 15(4), 1536 (2013). [Google Scholar] - 102.Zhou J, Krishnan N, Jiang Y, Fang RH, Zhang L. Nanotechnology for virus treatment. Nano Today 36, 101031 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 103.Zhang T, Sturgis TF, Youan BB. pH-responsive nanoparticles releasing tenofovir intended for the prevention of HIV transmission. Eur. J. Pharm. Biopharm. 79(3), 526–536 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar] - 104.Notario-Perez F, Cazorla-Luna R, Martin Illana Aet al. Design, fabrication and characterization of drug-loaded vaginal films: state-of-the-art. J. Control. Rel. 327, 477–499 (2020). [DOI] [PubMed] [Google Scholar] - 105.Fernandes T, Patel V, Aranha Cet al. pH-triggered polymeric nanoparticles-in-gel for preventing vaginal transmission of HIV and unintended pregnancy. Eur. J. Pharm. Biopharm. 191, 219–234 (2023). [DOI] [PubMed] [Google Scholar] - 106.Mishell DR Jr, Bell JH, Good RG, Moyer DL. The intrauterine device: a bacteriologic study of the endometrial cavity. Am. J. Obstet. Gynecol. 96(1), 119–126 (1966). [DOI] [PubMed] [Google Scholar] - 107.Pal Z, Urban E, Dosa E, Pal A, Nagy E. Biofilm formation on intrauterine devices in relation to duration of use. J. Med. Microbiol. 54(Pt 12), 1199–1203 (2005). [DOI] [PubMed] [Google Scholar] - 108.Mahamuni-Badiger PP, Patil PM, Badiger MVet al. Biofilm formation to inhibition: role of zinc oxide-based nanoparticles. Mater. Sci. Eng. C Mater. Biol. Appl. 108, 110319 (2020). [DOI] [PubMed] [Google Scholar] - 109.World Health Organization . Herpes simplex virus (2023). www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus - 110.Lewis RM, Laprise JF, Gargano JWet al. Estimated prevalence and incidence of disease-associated human papillomavirus types among 15- to 59-year-olds in the United States. Sex. Transm. Dis. 48(4), 273–277 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 111.Vassilopoulou L, Matalliotakis M, Zervou MIet al. Endometriosis and in vitro fertilisation. Exp. Ther. Med. 16(2), 1043–1051 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar] - 112.World Health Organisation . Infertility prevalence estimates, 1990–2021 (2023). www.who.int/publications-detail-redirect/978920068315 - 113.Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 2(8085), 366 (1978). [DOI] [PubMed] [Google Scholar] - 114.Szamatowicz M. Assisted reproductive technology in reproductive medicine – possibilities and limitations. Ginekol. Pol. 87(12), 820–823 (2016). [DOI] [PubMed] [Google Scholar] - 115.Ben-David Makhluf S, Qasem R, Rubinstein S, Gedanken A, Breitbart H. Loading magnetic nanoparticles into sperm cells does not affect their functionality. Langmuir 22(23), 9480–9482 (2006). [DOI] [PubMed] [Google Scholar] - 116.Makhluf SB, Abu-Mukh R, Rubinstein S, Breitbart H, Gedanken A. Modified PVA-Fe3O4 nanoparticles as protein carriers into sperm cells. Small 4(9), 1453–1458 (2008). [DOI] [PubMed] [Google Scholar] - 117.Barkalina N, Jones C, Kashir Jet al. Effects of mesoporous silica nanoparticles upon the function of mammalian sperm in vitro. Nanomedicine 10(4), 859–870 (2014). [DOI] [PubMed] [Google Scholar] - 118.Barkalina N, Jones C, Townley H, Coward K. Functionalization of mesoporous silica nanoparticles with a cell-penetrating peptide to target mammalian sperm in vitro. Nanomedicine 10(10), 1539–1553 (2015). [DOI] [PubMed] [Google Scholar] - 119.Thomson LK, Fleming SD, Aitken RJ, De Iuliis GN, Zieschang JA, Clark AM. Cryopreservation-induced human sperm DNA damage is predominantly mediated by oxidative stress rather than apoptosis. Hum. Reprod. 24(9), 2061–2070 (2009). [DOI] [PubMed] [Google Scholar] - 120.Falchi L, Galleri G, Dore GMet al. Effect of exposure to CeO2 nanoparticles on ram spermatozoa during storage at 4°C for 96 hours. Reprod. Biol. Endocrinol. 16(1), 19 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar] - 121.Mahdavinezhad F, Gilani MaS, Gharaei Ret al. Protective roles of seminal plasma exosomes and microvesicles during human sperm cryopreservation. Reprod. Biomed. Online 45(2), 341–353 (2022). [DOI] [PubMed] [Google Scholar] - 122.Holt WV. Fundamental aspects of sperm cryobiology: the importance of species and individual differences. Theriogenology 53(1), 47–58 (2000). [DOI] [PubMed] [Google Scholar] - 123.Hezavehei M, Sharafi M, Fathi R, Shahverdi A, Gilani MAS. Membrane lipid replacement with nano-micelles in human sperm cryopreservation improves post-thaw function and acrosome protein integrity. Reprod. Biomed. Online 43(2), 257–268 (2021). [DOI] [PubMed] [Google Scholar] - 124.Moce E, Blanch E, Tomas C, Graham JK. Use of cholesterol in sperm cryopreservation: present moment and perspectives to future. Reprod. Domest. Anim. 45(Suppl. 2), 57–66 (2010). [DOI] [PubMed] [Google Scholar] - 125.Ferreira G, Costa C, Bassaizteguy Vet al. Incubation of human sperm with micelles made from glycerophospholipid mixtures increases sperm motility and resistance to oxidative stress. PLOS ONE 13(6), e0197897 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar] - 126.Anastacio Da Silva E, Corcini CD, De Assis Araujo Camelo Junior Fet al. Probe ultrasonification of egg yolk plasma forms low-density lipoprotein nanoparticles that efficiently protect canine semen during cryofreezing. J. Biol. Chem. 298(7), 101975 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 127.Abbasi Y, Hajiaghalou S, Baniasadi F, Mahabadi VP, Ghalamboran MR, Fathi R. Fe3O4 magnetic nanoparticles improve the vitrification of mouse immature oocytes and modulate the pluripotent genes expression in derived pronuclear-stage embryos. Cryobiology 100, 81–89 (2021). [DOI] [PubMed] [Google Scholar] - 128.De Almeida Monteiro Melo Ferraz M, Fujihara M, Nagashima JB, Noonan MJ, Inoue-Murayama M, Songsasen N. Follicular extracellular vesicles enhance meiotic resumption of domestic cat vitrified oocytes. Sci. Rep. 10(1), 8619 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 129.Kuzmina TI, Chistyakova IV, Prituzhalova AO, Tatarskaya DN. The role of highly dispersed silica nanoparticles in the realization of the effects of granulosa on the maturation and fertilization competence of Sus scrofa domesticus oocytes. Vavilovskii Zhurnal Genet. Selektsii 26(3), 234–239 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 130.Khosla K, Wang Y, Hagedorn M, Qin Z, Bischof J. Gold nanorod induced warming of embryos from the cryogenic state enhances viability. ACS Nano 11(8), 7869–7878 (2017). [DOI] [PubMed] [Google Scholar] - 131.Khosla K, Kangas J, Liu Yet al. Cryopreservation and laser nanowarming of zebrafish embryos followed by hatching and spawning. Adv. Biosyst. 4(11), e2000138 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 132.Fayazi S, Damvar N, Molaeian Set al. Thermally conductive graphene-based nanofluids, a novel class of cryosolutions for mouse blastocysts vitrification. Reprod. Biol. 22(2), 100635 (2022). [DOI] [PubMed] [Google Scholar]; •• Heating and cooling rates limit embryo cryopreservation. This paper describes the use of nanofluid cryosolutions in vitrification, showing significantly reduced oxidative stress in mouse blastocysts compared with the usual sucrose-based solutions. - 133.Liu L, Johnson HL, Cousens Set al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379(9832), 2151–2161 (2012). [DOI] [PubMed] [Google Scholar] - 134.Blencowe H, Cousens S, Chou Det al. Born too soon: the global epidemiology of 15 million preterm births. Reprod. Health 10(Suppl. 1), S2 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar] - 135.US Food and Drug Administration (2023). https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-announce-decision-withdraw-approval-makena - 136.Refuerzo JS, Leonard F, Bulayeva Net al. Uterus-targeted liposomes for preterm labor management: studies in pregnant mice. Sci. Rep. 6, 34710 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar] - 137.Giusto K, Patki M, Koya Jet al. A vaginal nanoformulation of a SphK inhibitor attenuates lipopolysaccharide-induced preterm birth in mice. Nanomedicine 14(21), 2835–2851 (2019). [DOI] [PubMed] [Google Scholar] - 138.Patki M, Giusto K, Gorasiya S, Reznik SE, Patel K. 17-alpha hydroxyprogesterone nanoemulsifying preconcentrate-loaded vaginal tablet: a novel non-invasive approach for the prevention of preterm birth. Pharmaceutics 11(7), doi: 10.3390/pharmaceutics11070335 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 139.Hoang T, Zierden H, Date Aet al. Development of a mucoinert progesterone nanosuspension for safer and more effective prevention of preterm birth. J. Control. Rel. 295, 74–86 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 140.Zierden HC, Ortiz JI, Delong Ket al. Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth. Sci. Transl. Med. 13(576), doi: 10.1126/scitranslmed.abc6245 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 141.Najahi-Missaoui W, Arnold RD, Cummings BS. Safe nanoparticles: are we there yet? Int. J. Mol. Sci. 22(1), doi: 10.3390/ijms22010385 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 142.Brohi RD, Wang L, Talpur HSet al. Toxicity of nanoparticles on the reproductive system in animal models: a review. Front. Pharmacol. 8, 606 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar] - 143.Bartneck M, Ritz T, Keul HAet al. Peptide-functionalized gold nanorods increase liver injury in hepatitis. ACS Nano 6(10), 8767–8777 (2012). [DOI] [PubMed] [Google Scholar] - 144.Xu S, Zhang Z, Chu M. Long-term toxicity of reduced graphene oxide nanosheets: effects on female mouse reproductive ability and offspring development. Biomaterials 54, 188–200 (2015). [DOI] [PubMed] [Google Scholar] - 145.De Jong WH, Borm PJ. Drug delivery and nanoparticles: applications and hazards. Int. J. Nanomed. 3(2), 133–149 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar] - 146.Carlson C, Hussain SM, Schrand AMet al. Unique cellular interaction of silver nanoparticles: size-dependent generation of reactive oxygen species. J. Phys. Chem. B 112(43), 13608–13619 (2008). [DOI] [PubMed] [Google Scholar] - 147.Bruna T, Maldonado-Bravo F, Jara P, Caro N. Silver nanoparticles and their antibacterial applications. Int. J. Mol. Sci. 22(12):7202 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 148.Elder A, Gelein R, Silva Vet al. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ. Health Perspect. 114(8), 1172–1178 (2006). [DOI] [PMC free article] [PubMed] [Google Scholar] - 149.Olufunmilayo E, Gerke-Duncan M, Holsinger R. Oxidative stress and antioxidants in neurodegenerative disorders. Antioxidants (Basel) 12(2), 517 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar] - 150.Wang Z, Wang Z. Nanoparticles induced embryo-fetal toxicity. Toxicol. Ind. Health 36(3), 181–213 (2020). [DOI] [PubMed] [Google Scholar] - 151.Sun J, Mao B, Wu Zet al. Relationship between maternal exposure to heavy metal titanium and offspring congenital heart defects in Lanzhou, China: a nested case–control study. Front. Public Health 10, 946439 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 152.Gurunathan S, Kang MH, Jeyaraj M, Kim JH. Differential cytotoxicity of different sizes of graphene oxide nanoparticles in Leydig (TM3) and Sertoli (TM4) cells. Nanomaterials (Basel) 9(2), doi: 10.3390/nano9020139 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] - 153.Zhang XF, Choi YJ, Han JWet al. Differential nanoreprotoxicity of silver nanoparticles in male somatic cells and spermatogonial stem cells. Int. J. Nanomed. 10, 1335–1357 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar] - 154.Iftikhar M, Noureen A, Uzair M, Jabeen F, Abdel Daim M, Cappello T. Perspectives of nanoparticles in male infertility: evidence for induced abnormalities in sperm production. Int. J. Environ. Res. Public Health 18(4), doi: 10.3390/ijerph18041758 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar] - 155.Santonastaso M, Mottola F, Colacurci Net al. In vitro genotoxic effects of titanium dioxide nanoparticles (n-TiO2) in human sperm cells. Mol. Reprod. Dev. 86(10), 1369–1377 (2019). [DOI] [PubMed] [Google Scholar] - 156.Pinho AR, Rebelo S, Pereira ML. The impact of zinc oxide nanoparticles on male (in)fertility. Materials (Basel) 13(4), doi: 10.3390/ma13040849 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar] - 157.Wang J, Zhu X, Zhang Xet al. Disruption of zebrafish (Danio rerio) reproduction upon chronic exposure to TiO2 nanoparticles. Chemosphere 83(4), 461–467 (2011). [DOI] [PubMed] [Google Scholar] - 158.Mawed SA, Marini C, Alagawany Met al. Zinc oxide nanoparticles (ZnO-NPs) suppress fertility by activating autophagy, apoptosis, and oxidative stress in the developing oocytes of female zebrafish. Antioxidants (Basel) 11(8), doi: 10.3390/antiox11081567 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar] - 159.Preaubert L, Courbiere B, Achard Vet al. Cerium dioxide nanoparticles affect in vitro fertilization in mice. Nanotoxicology 10(1), 111–117 (2016). [DOI] [PubMed] [Google Scholar] - 160.Ingato D, Lee JU, Sim SJ, Kwon YJ. Good things come in small packages: overcoming challenges to harness extracellular vesicles for therapeutic delivery. J. Control. Rel. 241, 174–185 (2016). [DOI] [PubMed] [Google Scholar] - 161.Clayton A, Harris CL, Court J, Mason MD, Morgan BP. Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59. Eur. J. Immunol. 33(2), 522–531 (2003). [DOI] [PubMed] [Google Scholar] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article.