Nanotechnology in reproductive medicine: from gamete engineering to precision therapeutics

Xu Wen: conceptualization, formal analysis, investigation, writing – original draft; Zhiyan Wang: writing, visualization, validation, data curation; Jiahui Lin: visualization, validation, data curation; Longjie Li: material construction, analysis; Haiyun Wang: validation; Pei Liu: investigation; Hao Hu: visualization; Chao He: resources; Zijia Zheng: data curation; Ruisi Liu: investigation; Kejun Dong: methodology, writing – review & editing; Donghui Huang: methodology, writing – review & editing; Xianjin Xiao: methodology, supervision, writing – review & editing, funding acquisition, resources.

Oocyte quality is a primary determinant of female reproductive potential. During ART procedures, oxidative stress induced by in vitro manipulation remains a significant factor limiting IVF success rates. 72 Nanotechnology, with its efficient and targeted delivery capabilities, offers novel solutions to overcome this technical bottleneck. 73 In promoting oocyte maturation, exosomes facilitate ovarian cell expansion and nuclear maturation by delivering natural regulatory factors. 74 Furthermore, synthetic nanocarriers can effectively enhance oocyte quality by precisely modulating cell membrane potential and delivering artificially loaded antioxidants. 75 In cryopreservation, the photothermal effect of nanoparticles effectively suppresses ice crystal damage, offering a safer and more efficient solution for fertility preservation. 76 This section will explore research advances in nanotechnology for oocyte maturation, ovarian microenvironment regulation, and cryopreservation, providing an in-depth analysis of its prospects for clinical translation to offer new perspectives and approaches for reproductive medicine development. Gamete quality is a critical determinant of fertilized embryo developmental potential. Oocyte quantity and quality directly influence female fertility and pregnancy outcomes. 77 Despite significant advances in ART, in vitro manipulation of gametes may induce oocyte oxidative stress, 78 thereby compromising the success rates of IVF. Achieving precise delivery of substances into germ cells without compromising their developmental potential remains a key challenge for advancing reproductive biology and optimizing ART techniques. 79 Against this backdrop, nanotechnology demonstrates broad application potential in reproductive medicine due to its non-invasive and highly targeted characteristics. Oocytes communicate with surrounding cells through multiple pathways to promote developmental maturation. Exosomes, as secreted vesicular structures, are present at various stages of oocyte development and maturation. 80 Follicular fluid contains diverse exosomes whose miRNAs, proteins, lipids, and other constituents influence gene expression and participate in oocyte development regulation. 81 Follicular fluid-derived extracellular vesicles (FF-EVs) promote oocyte maturation by delivering regulatory factors. Hung et al. co-cultured mouse COCs with bovine-derived FF-EVs, observing that FF-EVs induced cumulus cell migration and extracellular matrix remodeling by delivering inducers such as Ptgs2, Ptx3, and Tnfaip6, thereby supporting cumulus cell expansion. 82 Ávila et al. discovered that vesicles with low progesterone levels are enriched with miRNAs regulating processes including MAPK, Hippo signaling pathways, and oocyte meiosis. These miRNAs can upregulate differentiation genes GDF9, ZP3, immune response-related genes IL6 and ARG1, and Notch signaling (HEY1)-related genes in cumulus cells. The miRNA composition of FF-EVs dynamically changes with the estrus cycle, offering a novel strategy for enhancing oocyte maturation in vitro . 83 Exosomes are not only present in follicular fluid but also originate from the oviduct, uterus, vagina, and other reproductive tissues, playing crucial roles in gamete development, fertilization, and pregnancy. However, the specific markers for the isolation and purification of these exosomes require further investigation, and the large-scale acquisition of naturally sourced exosomes remains challenging. Therefore, further exploration of specific markers for various types of exosomes to expand their production scale is an urgent issue to be addressed ( Fig. 2A-a ). Over recent years, research into organic nanoparticles, including natural polymer scaffolds and liposomes, has attracted considerable interest. Chitosan-based nanocarriers, featuring a hydrophobic core and hydrophilic shell, effectively encapsulate hydrophobic drugs and prolong their distribution time, making them efficient drug carriers. Hashem et al. constructed chitosan-TPP nanoparticles to encapsulate and deliver gonadotropin-releasing hormone (GnRH). They observed that injection of this complex increased corpus luteum numbers, significantly elevated serum estradiol (E2) and progesterone (P4) concentrations, and promoted oocyte maturation. 84 Xi H. et al. employed bilirubin-conjugated glycosylated chitosan (MB@GBn) as an outer layer to self-assemble endogenous bilirubin and melatonin, thereby alleviating oxidative stress during in vitro maturation (IVM) of oocytes. 85 Noori et al. developed melatonin-loaded nanostructured lipid carriers (Mel-NLCs), validating their efficacy in enhancing oocyte maturation within an IVF environment. Mel-NLCs demonstrated a burst release of melatonin within the first two hours, followed by sustained release over 48 hours, significantly prolonging drug delivery duration compared to commercially available suspension formulations. 86 Li et al. employed a peptide nanoparticle-mediated antibody transfection approach to deliver anti-Arl2 antibodies, successfully achieving specific inhibition of Arl2 in mouse oocytes. This method proves suitable for difficult-to-transfect cell types and can be extended to siRNA delivery, broadening its application scope. 87 These organic nanoparticles promote oocyte maturation through targeted delivery of antioxidants and transfection of antibodies to regulate gene expression, serving as effective regulatory strategies in IVM to enhance ART efficacy. Numerous other polymeric scaffolds, such as poly(lactic- co -glycolic acid) (PLGA), hyaluronic acid, and chondroitin sulphate derivatives, have demonstrated excellent drug-carrying capacity and biocompatibility. 88,89 Future research may develop additional polymeric nanoscale scaffolds encapsulating hormones to improve oocyte quality further. Regarding cell transfection methods, exemplified by peptide nanoparticles, regulating core genes and key proteins involved in oocyte maturation could expand their developmental potential ( Fig. 2A-b ). Metal nanoparticles promote follicular growth and enhance oocyte quality by modulating oxidative stress and improving oocyte structure. Fatemi et al. demonstrated that curcumin-loaded superparamagnetic Fe 3 O 4 nanoparticles promoted follicular growth in a polycystic ovary mouse model. They reduced apoptosis-associated proteins while increasing survival-associated protein Bcl-2, thereby facilitating natural ovulation and pregnancy, and promoting healthy offspring. 90 CeO 2 NPs engineered by Zhang D. M. et al. , incorporating alpha-lipoic acid and polyethene glycol modifications, demonstrated potent ROS scavenging capacity, reduced oocyte fragmentation, enhanced fertilization capacity and blastocyst development rates, whilst exhibiting favorable biocompatibility. 91 Majidi et al. 's research indicates that combined l -carnitine and ZnONPs treatment in diabetic rats enhances antioxidant activity and significantly increases follicle count. 92 Quintão et al. found ZnONPs mitigate oxidative stress damage to oocytes and increase oocyte numbers. 93 Nguyen et al. indicated that gold nanoparticles (AuNPs) could enhance stability through surface modification, carry multiple payloads, and serve as IVM medium supplements to improve assisted reproductive efficiency. 94 However, safety concerns regarding metallic nanomaterials are growing. ZnONPs show toxicity to ovarian germ cells, 95 copper oxide nanoparticles (CuONPs) damage mitochondria and impair oocyte maturation. 96 Furthermore, silver nanoparticles (AgNPs), titanium dioxide nanoparticles (TiO 2 NPs), and silica nanoparticles (SiO 2 NPs) may all induce abnormal hormone secretion, trigger oxidative stress, disrupt follicular development, and even cause infertility. 97 Therefore, future efforts should focus on evaluating the safety of these nanoparticles, optimizing their performance, and exploring the feasibility of clinical applications ( Fig. 2A-c ). The ovarian microenvironment provides nutrients and signals to follicles, influencing their growth and maturation. Its composition includes the extracellular matrix (ECM), ovarian stromal cells, and ovarian stem cells. 98 The ECM supports follicular development and capillary formation, playing a crucial role in corpus luteum formation. Ovarian stromal cells and stem cells also exert a significant influence on follicular development and functional maintenance. 99 Pathological alterations encompass ECM fibrosis, impaired angiogenesis, and cellular senescence. 100 Fibrosis impairs ovulation and endocrine function, stem cell depletion and senescence generate a pro-inflammatory microenvironment that compromises ovarian function. 101,102 These changes interact synergistically to accelerate ovarian functional decline. Nanotechnology can improve the ovarian microenvironment, with exosomes serving as natural carriers transporting multiple molecules to promote cellular repair and angiogenesis. 103 3D scaffold nanotechnology mimics the ovarian microenvironment, supporting follicular survival and development. Combined application holds promise as a novel approach for treating ovarian failure and improving fertility. 104 Exosomes significantly promote ovarian angiogenesis by regulating the expression of factors like VEGF. Research by Yang et al. demonstrated that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-exos), carrying VEGF-R2, MCP-1, and VEGF, can upregulate VEGF, IGF-1, and Angiogenin in mouse ovaries. They activate the PI3K/AKT pathway to exert a pro-angiogenic effect on ovarian microvasculature. 105 Qu et al. investigated the impacts of hUCMSC-exos on ovarian granulosa cells in a premature ovarian failure model. They discovered that miR-126-3p contained within the exosomes could upregulate VEGF, IGF-1, and FGF, thereby promoting angiogenesis, inhibiting apoptosis, and improving ovarian function. 106 Exosomes can also optimize the ovarian microenvironment by improving the immune microenvironment, reducing inflammation, and enhancing cellular vitality. Eslami N. et al. evaluated the effects of distinct exosome subpopulations (EV20K and EV110K) derived from cloned mesenchymal stem cells (cMSC-exos) on restoring function in prematurely aged ovaries. They found exosomes acted on granulosa cells and the ovarian microenvironment, reducing inflammatory factors, activating the PI3K/AKT pathway, and promoting angiogenesis. 107 These studies show that exosomes offer practical approaches for improving the ovarian microenvironment through mechanisms like antioxidant effects and enhancement of the microenvironment ( Fig. 2B ). 3D scaffolds support follicular cells, effectively maintaining follicular structure and intercellular interactions, and are suitable for culturing large-volume human follicles. 108 Compared to traditional 2D culture, 3D systems better mimic the in vivo microenvironment and preserve cell–matrix interactions. 109 Moreover, 3D culture systems can replicate multiple processes within the microenvironment, including soluble signaling, cell migration, and tissue development. 110 Gels, fibrin, and electrospun fibers can all serve as 3D scaffolds, recreating the natural biochemical environment of follicles within the ovary to establish an optimized microenvironment for in vitro culture ( Fig. 2C ). Gel scaffolds provide structural support for cells and tissues, rendering them suitable for follicular culture. Scaffold design employs not only highly biocompatible materials but also facilitates nutrient diffusion and metabolic waste clearance. 111 Felder et al. constructed porous alginate hydrogel scaffolds combined with bone morphogenetic protein-4 (BMP-4) self-assembled nanocomposites. 112 Compared to conventional alginate scaffolds, this scaffold exhibits enhanced loading capacity and prolongs the release duration of BMP-4 in culture medium. In vitro culture results demonstrated the scaffold's successful support of follicular growth, increased follicular numbers, and promotion of follicular maturation. In vivo transplantation experiments further revealed the scaffold's favorable efficacy in facilitating early microenvironment vascularization ( Fig. 2C-a ). The integration of stem cell technology with 3D scaffolds offers novel approaches for ovarian repair. Jiao et al. investigated the therapeutic efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) combined with hyaluronic acid (HA) gel in mice with premature ovarian failure. UC-MSCs activated the PI3K-AKT pathway via HGF and inhibited mTOR, while HA prolonged their retention time within the ovary. This system provides a novel strategy for MSC-based treatment of ovarian ageing 113 ( Fig. 2C-b ). With advances in materials science, smart responsive hydrogels demonstrate immense application potential. Shi et al. developed a novel hydrogel capable of releasing inhibitors upon RTK activation, thereby reducing mTOR activity, protecting ovarian cells, promoting microvascular formation, and delaying ageing. Its high targeting specificity and low dosage render it suitable for treating premature ovarian failure and ageing. 114 Yang et al. combined hydrogels with fibrin to encapsulate nitric oxide (NO) nanoparticles within the hydrogel matrix. This approach effectively promoted vascularization in transplanted ovaries, enhancing both the quantity and quality of follicles within the graft. It successfully supported the in vitro fertilization process and blastocyst formation of oocytes 115 ( Fig. 2C-c ). Electrospinning, a technique employing high-voltage electric fields to produce ultrafine fibers, demonstrates potential in ovarian tissue engineering by improving follicular adhesion and survival. 116 This method mimics the ovarian extracellular matrix, facilitates cell interactions, and provides an appropriate microenvironment for cells. L. Liverani et al. employed electrospinning to fabricate PCL/gelatin scaffolds with nanoscale pores, exhibiting superior three-dimensional architecture. These scaffolds facilitate follicular attachment, growth, and proliferation, thereby boosting follicular survival rates and promoting vascularization to repair damaged ovaries structures 117 ( Fig. 2C-d ). The successful application of the matrix above provides a research direction for next-generation advanced follicular culture systems. Nevertheless, fibrin degrades readily in vitro , potentially compromising the scaffold's capacity to support follicular development. Enhancing its biostability thus remains an urgent technical difficulty. 118 Existing electrospinning techniques cannot precisely control fiber diameter, leaving the precise construction of nanofibers an unresolved challenge. 119 Furthermore, their biodegradability and biosafety require further clarification. Selecting suitable materials to ensure degradation rates and safety remains a considerable undertaking. In recent years, demand for fertility preservation has significantly increased due to malignant tumors, benign conditions, societal factors, and age-related fertility decline. 120 Currently, embryo cryopreservation, oocyte cryopreservation following ovarian stimulation, and ovarian tissue cryopreservation are the three mainstream fertility preservation strategies recommended by the American Society for Reproductive Medicine. 121 Among these, oocyte cryopreservation is increasingly sought as societal acceptance and insurance coverage expand. 122 Nanotechnology shows promise in this field by enabling dynamic regulation of cryopreservation parameters, enhancing efficiency and reducing cryoinjury. 123 Through optimized material properties, it can improve the cryoprotective microenvironment. 124 Oocyte cryopreservation achieves long-term preservation of female fertility by suppressing cellular metabolism and biochemical reactions under ultra-low temperatures. 125 Commonly employed cryopreservation methods include programmed slow-freezing and vitrification. Slow-freezing techniques control cooling rates to minimize intracellular and extracellular ice crystal formation, although improper rates may cause cellular damage. 126 In contrast, vitrification employs extremely rapid cooling to form an amorphous glassy state, effectively preventing ice crystal damage and is widely recognized as one of the most efficient cryopreservation methods currently available. 127 Nevertheless, this technique still faces challenges in controlling ice crystal formation and optimizing the thawing process. Minimizing ice crystal formation is a critical step in the cryopreservation process. Crystallization not only causes mechanical damage to cell membranes but may also disrupt intracellular macromolecular structures. Research indicates that effective control of ice crystal formation enhances oocyte survival rates and embryo developmental capacity, 128 thereby mitigating adverse effects on post-thaw IVF outcomes. Consequently, developing nanomaterials to inhibit ice crystal formation has become a research focus. Graphene oxide (GO) is a novel material exhibiting excellent ice crystal suppression capabilities. H. Geng et al. discovered that GO binds to the basal or prismatic faces of ice crystals, causing surface curvature that lowers the freezing point and inhibits crystal growth. Molecular dynamics simulations reveal that carboxyl groups on GO surfaces form more hydrogen bonds with ice than with liquid water, providing a reliable molecular mechanism for controlling ice crystal formation. 129 Furthermore, oxide quasi-carbon nitride quantum dots (OQCNs) and zirconium-based metal–organic framework (MOF) nanoparticles have also been demonstrated to effectively inhibit ice crystals and enhance cell survival rates. 130 OQCNs exhibit thermal hysteresis effects and morphoregulatory capabilities in ice, whilst MOFs demonstrate application value in cellular cryopreservation by inhibiting ice recrystallization and promoting ice crystal melting. Baniasadi et al. investigated the effects of static magnetic fields (SMF) and iron oxide nanoparticles on the vitrification of cumulus oocyte complexes (COCs). Their findings indicate that the combination of SMF and nanoparticles restored the normal expression of key genes, such as Cdx2, effectively mitigating cryoinjury and significantly enhancing the developmental potential and blastocyst formation rates of the COCs 131 ( Fig. 2D ). Thawing rate directly impacts cell survival and functional recovery. To enhance thawing efficiency and uniformity, researchers have developed and applied multiple nano-assisted thawing techniques. In magnetothermal rewarming, J. Pan et al. designed an electromagnetic resonance rewarming system incorporating magnetic nanoparticles (MNPs) to enhance energy absorption and conversion. This achieved rewarming rates exceeding 200 °C min −1 and successfully rewarmed milliliter-scale samples. The use of extremely low MNP concentrations (0.1 mg per mL Fe) suggests potential for its application in tissue and organ preservation. 132 A. Ito et al. achieved uniform rapid rewarming using MNPs, significantly improving survival rates in large-volume specimens 133 ( Fig. 2E-a ). Photothermal rewarming technology employs the photothermal effect of nanoparticles to elevate temperature, preventing ice crystal reformation rapidly. K. Khosla et al. utilized gold nanorods and laser pulses to rewarm zebrafish embryos, achieving survival rates comparable to unfrozen controls, with some individuals developing into reproductive adults. 134 Y. Hou et al. developed a photothermal rewarming system based on liquid metal nanoparticles, significantly enhancing rewarming rates and tissue survival under low cryoprotectant concentrations while demonstrating excellent biocompatibility 135 ( Fig. 2E-b ). Research integrating magnetic-thermal and photothermal advantages has enhanced rewarming performance. Tian et al. developed a low-toxicity vitrification method utilizing the dual thermal effects of GO and Fe 3 O 4 nanoparticles, enabling follicular precursors to retain morphology and function post-rewarming, ultimately yielding healthy offspring via in vitro fertilization. 136 Karimi et al. employed PEG-modified silica-coated iron oxide nanoparticles to thaw ovarian tissue within an alternating magnetic field. This approach markedly improved antioxidant markers, reduced apoptosis, and restored follicular development and associated gene expression to levels approaching those of fresh tissue 137 ( Fig. 2E-c ). The integration of nanomaterials with novel thawing techniques enhances oocyte cryopreservation efficacy. However, materials such as GO, OQCNs, Fe 3 O 4 and MOFs may exhibit cytotoxicity at high concentrations, necessitating further investigation into their biocompatibility, stability, and scalable production feasibility. Furthermore, achieving uniformity and rate control during thawing, particularly in large-volume samples, remains a technical challenge. Antioxidant strategies based on nanotechnology can significantly mitigate oxidative damage, improving the survival rate and developmental capacity of cryopreserved oocytes. Future work should elucidate their molecular mechanisms, optimize dosages and delivery systems, and evaluate the safety of nanomaterials. Advancing the integration of nanotechnology with antioxidant strategies will facilitate the establishment of more efficient and secure oocyte cryopreservation systems.

This review systematically underscores the transformative potential of nanotechnology as a frontier platform for addressing global infertility challenges. By facilitating precise antioxidant protection, targeted delivery of bioactive molecules, gene regulation, and high-throughput sperm screening, nanotechnology offers a paradigm shift to circumvent the intrinsic limitations of current ART—notably, the low efficacy in compromised gametes, cryoinjury susceptibility, and the lack of disease-specific therapeutics. In the realm of male reproductive health, nanomaterials such as CeO 2 NPs and SeNPs have been shown to significantly augment sperm motility, morphology, and DNA integrity by mimicking enzymatic activity to scavenge ROS. Furthermore, delivery systems based on exosomes or synthetic nanocarriers provide precise interventions for sperm dysfunction arising from genetic defects ( e.g. , Dmc1 or Pin1 deficiency) or acquired pathologies like varicocele. Concurrently, the integration of magnetic nanoparticles with microfluidics has propelled sperm sorting toward higher efficiency and reduced cellular damage. In female reproductive health, nanotechnology applications are equally diverse: stem cell-derived or follicular fluid exosomes effectively promote cumulus cell expansion and nuclear maturation. Similarly, chitosan- and liposome-based carriers successfully deliver agents such as melatonin and retinoic acid, thereby attenuating oxidative stress during IVM. Moreover, the capacity of nanomaterials to inhibit ice crystal formation and facilitate rapid, uniform rewarming significantly bolsters the efficiency of oocyte vitrification. Beyond therapeutics, nanotechnology demonstrates exceptional dual value in theranostics. Specifically, nanoprobe-based modalities, including NIR-II fluorescence and photoacoustic imaging, enable non-invasive, high-precision detection of pathologies such as endometriosis and hydrosalpinx. Meanwhile, nanocarrier systems—ranging from hydrogel nanoparticles to biomimetic vesicles—provide novel, low-toxicity therapeutic strategies for complex disorders like POI and PCOS by optimizing drug pharmacokinetics and targeting mechanisms. Despite these advances, translating nanotechnology from bench to bedside is impeded by significant hurdles. First, biosafety remains a primary concern; specific metallic nanoparticles ( e.g. , AgNPs and ZnONPs) exhibit cytotoxicity toward germ cells, necessitating comprehensive longitudinal evaluations of their in vivo metabolism, accumulation, and immunogenicity. Second, the lack of standardization and scalability presents a major bottleneck. Establishing large-scale, high-purity production processes for exosomes and complex nanomedicines is critical to guaranteeing quality control and batch consistency. Finally, clinical translational evidence is scarce. As most data are derived from animal models, rigorous clinical trials are imperative to validate safety and efficacy in humans, alongside the establishment of robust ethical and regulatory frameworks. Looking forward, the evolution of nanobiomedicine in reproduction should prioritize four key directions: firstly, material innovation. Designing novel nanomaterials with enhanced biocompatibility, biodegradability, and stimuli-responsive properties ( e.g. , pH- or enzyme-triggered release) to minimize off-target toxicity; secondly, mechanistic elucidation. Utilizing multi-omics and advanced imaging to decode the molecular interactions between nanomaterials, germ cells, and the reproductive microenvironment, thereby laying a theoretical foundation for rational design; thirdly, technological convergence. Integrating nanotechnology with artificial intelligence, CRISPR gene editing, and organ-on-a-chip platforms to construct high-fidelity in vivo -mimetic models and intelligent therapeutic systems; fourthly, clinical translation. Fostering interdisciplinary collaboration to initiate exploratory clinical studies targeting specific indications—such as idiopathic infertility and POI—while concurrently establishing standardized protocols for production and safety assessment. In summary, nanotechnology holds the promise to revolutionize the prevention, diagnosis, and treatment of reproductive disorders. Through sustained multidisciplinary innovation and prudent translation, this frontier technology may ultimately provide safer, more effective, and personalized fertility solutions for millions of couples worldwide.

The management of gynecological disorders, particularly those impacting reproductive function, presents substantial clinical challenges. 138 These stem from pathological complexity, limitations in targeted therapies, and the invasive nature of many procedures. 139 In this context, nanotechnology has emerged as a transformative frontier in biomedical science. It offers novel solutions through enhanced drug delivery, improved imaging, and innovative regenerative strategies. 140 Nanotechnology demonstrates distinct advantages. By utilizing platforms such as engineered extracellular vesicles and composite nanofiber scaffolds, 141 nanomaterials enable precise delivery of bioactive molecules to promote the restoration of ovarian function. Hydrogel systems can achieve minimally invasive repair of fallopian tube injuries. 142 In the context of endometriosis, nanotechnology further advances the development of non-invasive diagnostic techniques and targeted therapeutic strategies, such as intervening in disease progression through the modulation of glucose metabolism, attenuation of oxidative stress, and inhibition of angiogenesis. 143,144 These nano-based strategies offer more precise and minimally invasive diagnostic and therapeutic options for gynecological diseases. When integrated with existing clinical technologies, they hold significant potential for markedly improving fertility preservation and disease treatment outcomes. Premature ovarian insufficiency (POI) denotes ovarian dysfunction occurring before age 40, characterized by menstrual irregularities (amenorrhea or oligomenorrhoea) accompanied by elevated gonadotropin (Gn) levels and fluctuating estrogen decline. Unlike natural menopause in women, POI not only impacts fertility, psychological well-being, and quality of life but also poses significant risks to cardiovascular, urogenital, musculoskeletal, and cognitive health. Its etiology encompasses genetic, immunological, infectious, environmental, and iatrogenic factors, though precise mechanisms remain unclear. To date, no definitive method exists to restore ovarian function. Premature ovarian failure (POF) represents the terminal stage of POI primarily manifesting as amenorrhea before age 40, elevated Gn levels, and reduced estrogen levels, potentially accompanied by varying degrees of hypoestrogenic symptoms. 145 Both POI and POF represent significant causes of female infertility. Present-day clinical interventions, including hormone replacement therapy, ovulation induction, and stem cell transplantation, face limitations including inefficient drug delivery, inadequate targeting, and poor cell survival rates. In recent years, nanotechnology has demonstrated potential application value in ovarian function restoration due to its characteristics of precise delivery, controlled release, and multifunctional integration. For instance, Zhou et al. targeted immune pathways in POI pathogenesis by constructing a bioengineered nanoplatform using engineered extracellular vesicles as scaffolds to deliver PD-L1 and Gal-9. This approach inhibited ovarian autoimmunity and restored serum anti-Müllerian hormone (AMH) levels in a POI model, thereby halting disease progression and preserving ovarian function 146 ( Fig. 3A ). L. Yan et al. innovatively constructed graphene oxide/polylactic acid (GO/PLLA) composite nanofiber scaffolds. Using a mouse POF model, they investigated the efficacy of this nanomaterial encapsulating normal ovarian tissue for combined transplantation. Experiments demonstrated that co-transplantation of GO/PLLA material with ovarian tissue increased anti-Müllerian hormone (AMH) and estradiol (E2) levels while reducing follicle-stimulating hormone (FSH) levels. It also increased total follicle counts on both transplanted and non-transplanted sides. This innovative approach offers a novel strategy for preserving female fertility 147 ( Fig. 3B ). Guan et al. encapsulated the anti-ageing drugs dasatinib and quercetin within nanoparticles to enhance their water solubility. In a cyclophosphamide-induced POF model, the nano-encapsulated senolytic D + Q cocktail effectively improved the quality of aged oocytes and increased follicular numbers. Concurrently, it significantly reduced ROS levels, thereby mitigating DNA damage and apoptosis. This nanotechnology holds promise for improving POF and ART outcomes 148 ( Fig. 3C ). Although clinical research on nanotherapeutics for POI/POF remains in its infancy, nanotechnology explorations in other reproductive fields ( e.g. , endometriosis, polycystic ovary syndrome) have been extensively documented. Consequently, nanotherapeutic approaches for POI and POF are considered to possess considerable translational potential. 149 Polycystic ovary syndrome (PCOS) is a prevalent gynecological endocrine disorder characterized clinically by hyperandrogenism and ovulatory dysfunction. Conventional pharmacological treatments like clomiphene citrate and metformin show limited effectiveness due to poor drug targeting and significant side effects, highlighting the need for safer and more efficient therapies strategies. 150 In recent years, nanotechnology has demonstrated immense potential in the biomedical field due to its unique physicochemical properties and delivery advantages. Hydrogel nanoparticles offer significant advantages in treating polycystic ovary syndrome, owing to their unique three-dimensional network structure, which provides excellent drug-loading capacity, favorable targeting properties, outstanding biocompatibility, and degradability. Usulkar et al. enhanced the efficacy of nano-nanocapsules for treating PCOS by developing, evaluating, and refining a vaginal in situ gel containing, thus increasing drug penetration, achieve controlled release kinetics, and mitigate adverse reactions associated with oral berberine administration. 151 Farooq et al. designed a nano-biphasic formulation comprising metformin-loaded mucus-penetrating nanoparticles (MTF-MPP) and inositol-loaded mucus-penetrating particles (MI-MPP). Administered vaginally by mixing the biphasic formulation into a carbomer gel, in vivo studies compared this approach with conventional vaginal gels. This formulation significantly reduced ovarian weight while demonstrating non-irritant, safe therapeutic effects, thereby offering a promising strategy for vaginal drug delivery 152 ( Fig. 3D ). Conditions like PCOS, which are characterized by high levels of male hormones, often present with excessive hair growth. Amer et al. investigated the follicle-targeting effects of topical spironolactone (SP) versus progestogen-loaded (PG) nanostructured lipid carriers (NLCs) on hirsutism. And prepared SP-NLC and PG-NLC topical hydrogels to investigate their pharmacological effects on letrozole-induced PCOS in rats. Topical application of SP or PG nanogel resulted in significantly reduced hair follicle diameter and density. The impact of these locally administered nanostructured lipid carriers on hirsutism offers a potential therapeutic approach for PCOS 153 ( Fig. 3E ). Wang et al. synthesized two novel coordination polymers (CPs) containing Co( ii ), subsequently encapsulating these CPs within hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) hydrogels and ultimately yielding two types of metal gel particles carrying spironolactone (HA/CMCS-CPs@spironolactone). An in vitro PCOS cell model was established, and PCOS cells were treated with the metal gel particles. Levels of malondialdehyde (MDA), a key indicator of oxidative stress, were measured. Results demonstrated that both metal gel particles reduced MDA levels in a dose-dependent manner, offering a promising therapeutic option for PCOS. 154 Raja et al. developed curcumin (Cur)-encapsulated chitosan (Arg-CS-NAcHis/Cur) nanoparticles modified with arginine (Arg) and N -acetylhistidine (NAcHis). In vitro drug release experiments demonstrated sustained release from these nanoparticles, while cytotoxicity and cellular uptake studies showed superior efficacy compared to free curcumin. Biochemical and histopathological analyses confirmed the nanoparticle's positive effect on symptom recovery in PCOS rats. 155 Alwan et al. experimentally assessed the effects of Cinnamomum zeylanicum (CZ)-derived AgNPs on inflammatory cytokines in PCOS rats. They found that CZ-derived AgNPs may exert anti-inflammatory effects by reducing cytokine concentrations of TNF-α, IL-6, and IL-18 in PCOS rats 156 ( Fig. 3F ). Tubal diseases account for 25–35% of female infertility. As the site of fertilization is located within the female fallopian tubes, obstruction or pathological changes in this region inevitably reduce conception rates and may even cause infertility. 157 Consequently, diagnosing tubal patency and treating associated diseases holds significant value in infertility management. Currently, the primary clinical method for assessing fallopian tube patency is hysterosalpingography, which carries disadvantages including radiation exposure and a high false-positive rate. 158 Nanotechnology offers distinct advantages in non-invasive diagnostics, featuring excellent tissue penetration and low signal-to-noise ratios. Duan et al. synthesized a rare-earth erbium-based nanoprobe (Er-RENPs) with superior near-infrared II (NIR-II) fluorescence properties using NIR-II fluorescence imaging. This probe exhibits good biocompatibility and can clearly delineate fallopian tube contours, enabling diagnosis of narrowed, obstructed tubes and hydrosalpinx. It demonstrates significant application potential in diagnosing fallopian tube disorders 159 ( Fig. 4A ). Fallopian tube damage constitutes a significant factor in infertility. Common clinical treatments for tubal disorders include antibiotic therapy and laparoscopic surgery, which may lead to varying degrees of tubal adhesions and antibiotic resistance. 160 Although nanotechnology for treating tubal infertility remains in its infancy, it demonstrates formidable application potential. Current research primarily focuses on hydrogel systems. For instance, Luo et al. encapsulated dental pulp stem cells within hydrogels and performed in situ transplantation at sites of tubal injury to facilitate repair and regeneration. 161 Francés-Herrero and colleagues pursued an alternative approach by creating a fallopian tube-specific extracellular matrix (oviECM) hydrogel. Its rich bioactive components perfectly mimic the natural environment, thereby optimizing the developmental pathways for cultured embryos 162 ( Fig. 4B ). Endometriosis refers to the growth, infiltration, and recurrent bleeding of endometrial tissue (glands and stroma) outside the uterine cavity lining and myometrium. This can form nodules and masses, causing pain, infertility, and other complications. 163 Endometriosis ranks among the most prevalent conditions affecting women of reproductive age, with an incidence rate of approximately 10–15%. However, its prevalence rises to 20–25% among women experiencing infertility, exhibiting an upward trend. Diagnosis based on visual laparoscopy remains the gold standard for identifying and staging endometriosis. Laparoscopy is an invasive procedure; while relatively safe, surgical risks cannot be overlooked, including intraoperative hemorrhage, wound infection, and surrounding tissue adhesions. Even during surgery, the coloration of endometriotic lesions can present in multiple patterns, making intraoperative differentiation from normal tissue challenging. Thus, nanotechnology presents a promising solution for enhancing the intraoperative ability of gynecologists and surgeons to differentiate between benign and malignant tissues. Taratula et al. designed nanoparticles composed of the fluorescent dye naphthocyanine, which activate upon internalization by endometriotic cells, emitting a fluorescent signal to distinguish pathological from normal tissue. 164 These nanoparticles can also utilize the photothermal effect to interact with near-infrared light, enabling cellular ablation and thus achieving combined diagnostic and therapeutic objectives ( Fig. 4C ). Marquardt et al. developed a synthetic multimodal imaging technique utilizing fluorescein isothiocyanate gold nanoparticles to label endometriosis-like lesions. 165 Quanjie Lv et al. employed a poly- l -lysine-indocyanine green-hyaluronic acid nanoparticle formulation. By enhancing fluorescence photostability and antioxidant capacity, alongside low permeability and lesion surface retention properties, this approach provides novel experimental tools for investigating endometriosis and its associated infertility development 166 ( Fig. 4D ). Talebloo et al. successfully detected lesions in an endometriosis mouse model using cRGD-peptide-conjugated nanoparticles and magnetic resonance imaging technology. This technique enables in vivo photoacoustic imaging detection of gold-labelled lesions in the preclinical stage, with labelled tissues readily excised via fluorescence dissecting microscopy. It offers novel experimental approaches for studying and understanding the development and progression of endometriosis and associated infertility 167 ( Fig. 4E ). Current treatment modalities for endometriosis primarily encompass pharmacological interventions, surgical procedures, and ART. Pharmacological approaches predominantly involve hormonal agents and non-steroidal anti-inflammatory drugs (NSAIDs). While hormonal therapies may alleviate symptoms and control lesions by suppressing ovarian hormone secretion, long-term use carries risks of osteoporosis and mood fluctuations. Crucially, these treatments fail to address the underlying pathology, with lesions often recurring upon discontinuation. NSAIDs merely alleviate pain without significantly affecting the lesions themselves, whilst prolonged use may cause gastrointestinal discomfort or other side effects. 168 Removing or destroying ectopic endometrial tissue through surgery can help, but it also carries risks of complications like infection and scarring, and doesn't guarantee that the condition won't come back. Patients with severe endometriosis may undergo a total hysterectomy. This irreversible procedure significantly impacts physiological function and psychological well-being, and is unsuitable for women wishing to preserve fertility. 169 For people with endometriosis and infertility, ART like IVF offer the best solution. However, these techniques involve complex procedures, high costs, and success rates influenced by multiple factors. 170 Multiple studies indicate that nanotechnology may emerge as a novel therapeutic option for endometriosis. Among the various proposed etiologies, the retrograde menstrual implantation theory is widely accepted. Anthis et al. proposed a reversible contraceptive method by implanting a hydrogel system within a human-scale uterine model. 171 This hydrogel system comprises two distinct acrylamide polymers crosslinked with either the photolabile molecule poly(ethylene glycol) di-photodegradable acrylate (PEGdiPDA) or the disulphide crosslinker N , N ′-bis(acryloyl)cystamine (BAC), forming a hydrogel. The hydrogel system mechanically obstructs the fallopian tubes, whilst its biocompatibility was validated in a porcine model, enabling reversible sterilization and offering potential treatment for endometriosis ( Fig. 4F-a ). Hormonal therapy remains the standard pharmacological treatment for endometriosis, yet hormones inevitably carry numerous side effects and cause significant bodily trauma. There is an urgent need to develop specific therapeutics for endometriosis. Capitalizing on two characteristics—the persistent recruitment of neutrophils to ectopic lesions and the high glucose uptake of ectopic cells—Zhu et al. designed bovine serum albumin nanoparticles (BSA-GOx-NPs) loaded with glucose oxidase. These nanoparticles are delivered to ectopic lesions in a neutrophil-dependent manner with high specificity. They consume glucose to induce apoptosis in ectopic lesions, demonstrating efficacy against both acute and chronic inflammation 172 ( Fig. 4F-b ). Numerous studies indicate that oxidative stress is implicated in the pathogenesis of various diseases, including tumors, endometriosis, and certain cardiovascular and cerebrovascular disorders. In endometriosis patients, research demonstrates elevated oxidative stress levels, manifested as increased ROS production and diminished antioxidant capacity. These alterations not only promote the proliferation and migration of ectopic endometrial cells but also trigger local inflammatory responses, exacerbate pain, and impair reproductive function. Chaudhury et al. demonstrated that cerium oxide nanoparticles alleviate endometrial lesions induced in mouse models by reducing oxidative stress and inhibiting angiogenesis. Furthermore, these nanoparticles protect oocytes from endometriosis effects 173 ( Fig. 4F-c ). Sun et al. prepared acid-sensitive calcium carbonate nanoparticles (CaNP) doped with BML-111 (BML@CaNP). BML@CaNP enhances macrophage phagocytosis in a calcium ion-dose-dependent manner. Concurrently, the calcium carbonate nanoparticles synergistically exert anti-inflammatory effects with the endogenous pro-resolving lipid mediator Lipoxin A4 (LXA4), primarily through BML-111's role as a Lipoxin agonist 174 ( Fig. 4F-d ). Gene therapy demonstrates unique advantages in treating endometriosis, particularly regarding targeting precision, personalization, and sustained efficacy. Small interfering RNA (siRNA), as a gene therapy modality, can selectively silence any gene by interfering with mRNA expression. However, siRNA is a negatively charged macromolecule that struggles to traverse cell membranes; nanoparticle encapsulation technology overcomes this challenge. K. Kiisholts et al. discovered that RGD1-R6 peptide carriers can polymerize with siRNA to form stable nanoparticles. This nanoparticle complex was surgically administered in rat models to induce RNAi-mediated silencing of the VEGFA gene, thereby exerting anti-angiogenic effects. 175 MiRNAs play crucial roles in gene expression and are highly correlated with the pathogenesis of certain diseases. S. Chaichian et al. developed poly(lactic- co -glycolic acid) copolymer nanoparticles (PLGA-NPs) to deliver miRNA-503 to endometriotic cyst stromal cells, thereby suppressing endometriotic cell proliferation and enhancing apoptosis 176 ( Fig. 4F-e ). Nanoparticle therapy demonstrates promising prospects in the intervention of endometriosis, offering potential as a significant future therapeutic strategy for this condition.

Reproductive dysfunction and consequent infertility in both sexes have emerged as escalating global public health challenges, profoundly impacting individual reproductive goals, familial well-being, and population stabilitystitutes the cornerstone of reproductive health. Specifically, sperm parameters (motility, morphology, and DNA integrity) and oocyte developmental competence are critical determinants of successful fertilization, embryogenesis, and clinical pregnancy outcomes. 1 However, gamete integrity and function are vulnerable to a myriad of intrinsic and extrinsic insults. Factors such as oxidative stress, genetic aberrations, environmental pollutants, age-related decline, and adverse lifestyle habits can compromise these cells, thereby serving as primary drivers of fertility disorders. 2 Infertility stemming from compromised gamete quality remains a persistent clinical challenge. While assisted reproductive technologies (ART)—notably in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)—have revolutionized the management of infertility, current therapeutic frameworks are constrained by inherent limitations. Standard protocols are not only intricate and cost-prohibitive but are also contingent upon baseline sperm parameters. Consequently, clinical efficacy is often compromised in cases of severe asthenozoospermia, teratozoospermia, or idiopathic etiologies. Furthermore, critical bottlenecks remain regarding the efficiency of in vitro maturation (IVM), the preservation of gamete viability during cryopreservation, and the mitigation of inflammation within the reproductive tract. 3 Against this backdrop, nanotechnology has garnered significant attention owing to its unique physicochemical versatility. Key attributes—including ultra-high specific surface area, tunable surface chemistry, biocompatibility, and superior drug-loading capacity—render nanomaterials particularly suitable for reproductive applications. 4 Emerging research highlights the therapeutic potential of these materials in preserving gamete competence. For instance, antioxidant nanoparticles effectively scavenge excessive ROS, thereby mitigating oxidative damage to gametes. 5 Furthermore, delivery systems utilizing liposomes, polymeric nanoparticles, or exosomes enable the precise transport of bioactive payloads, such as hormones, growth factors, and gene regulatory elements. These platforms have been shown to enhance oocyte maturation, optimize cryoprotection protocols, and support early embryogenesis. 6 Beyond these applications, nanotechnology is driving advances in high-throughput sperm sorting, the modulation of the ovarian microenvironment, and targeted pharmacotherapy within the reproductive tract. Several previous reviews have discussed the application of nanotechnology in reproductive medicine, medically assisted reproduction, infertility treatment, and female reproductive healthcare. Earlier work introduced the emerging use of nanomaterials in reproductive biology and clinical reproductive medicine, while subsequent reviews emphasized ART-related applications, clinical translation opportunities, and the benefits and challenges of nanomaterials in assisted reproduction. 7–11 More recent reviews have further summarized nanoparticles in women's reproductive health and broader reproductive healthcare, including applications in PCOS, endometriosis, uterine disorders, sexually transmitted infections, imaging, and drug delivery. 12,13 Nevertheless, many existing reviews focus on either general reproductive nanomedicine, selected ART procedures, or specific female reproductive diseases. A materials-centered and disease-integrated synthesis that links nanoplatform design, gamete quality control, reproductive microenvironment regulation, safety considerations, and translational barriers across both male and female infertility remains relatively limited. In this review, we systematically summarize recent advances in nanotechnology for optimizing gamete quality and improving the diagnosis and management of reproductive disorders. Compared with previous reviews, the present article emphasizes the continuum from gamete engineering to precision therapeutics, covering sperm quality improvement, sperm selection, oocyte maturation, cryopreservation, ovarian dysfunction, polycystic ovary syndrome, tubal disease, and endometriosis. Particular attention is given to the chemistry and materials science aspects of representative nanoplatforms, including material composition, particle size, surface functionalization, loading capacity, release behavior, biodegradability, and structure–activity relationships. We further evaluate their mechanisms of action, therapeutic efficacy, limitations, reproductive safety concerns, scalability, and translational readiness. By integrating material design, reproductive biology, preclinical evidence, and clinical barriers, this review aims to provide a balanced framework for the rational development and cautious clinical translation of nanotechnology-enabled reproductive medicine. To facilitate cross-platform comparison, a comprehensive summary of representative nanoplatforms is provided in Table S1 (SI).

The authors declare no conflict of interests.

Despite the rapid expansion of nanotechnology in reproductive medicine, the translation of these approaches into clinical practice remains limited. Compared with other biomedical fields, reproductive medicine imposes uniquely stringent requirements, as interventions may affect not only somatic tissues but also gametes, embryos, pregnancy outcomes, and potentially the health of future generations. Therefore, in addition to demonstrating therapeutic efficacy, nanoplatforms must meet higher standards of safety, reproducibility, and long-term biological compatibility. Among the diverse nanotechnologies discussed in this review, their translational readiness varies substantially. Ex vivo approaches, particularly those integrated into ART workflows, are relatively closer to clinical application. Microfluidic sperm selection systems and MACS, for example, have already been explored in clinical or laboratory settings to enrich sperm populations with improved motility and reduced DNA fragmentation. Because these strategies operate outside the human body, systemic exposure is minimized, which may facilitate regulatory approval. However, their impact on clinically meaningful endpoints, such as cumulative live birth rates and long-term offspring outcomes, still requires further validation. Nano-enabled cryopreservation systems and antioxidant nanomaterials also show translational promise in the context of gamete and embryo handling. By reducing oxidative stress and cryoinjury, these approaches may improve fertilization efficiency and embryo developmental competence. Nevertheless, uncertainties remain regarding optimal dosing, nanoparticle retention, and potential effects on early embryogenesis. In contrast, most in vivo nanotherapeutic strategies, including nanoparticle-based drug delivery for ovarian dysfunction, PCOS, endometriosis, and tubal disease, are still largely confined to preclinical studies. Although these systems offer advantages such as targeted delivery, controlled release, and improved bioavailability, their clinical translation is constrained by challenges related to biodistribution, pharmacokinetics, interspecies variability, and safety in the reproductive context. Biologically derived nanoplatforms, such as EVs, represent a promising emerging direction due to their intrinsic biocompatibility and ability to mediate intercellular communication. However, their translation is currently limited by difficulties in large-scale production, heterogeneity, and lack of standardized characterization methods. Safety considerations are particularly critical in reproductive nanomedicine. Unlike conventional therapeutic areas, where short-term efficacy and toxicity are often the primary concerns, reproductive applications require comprehensive evaluation across multiple biological levels. At the gonadal level, nanoparticles may interact with spermatogenic cells, oocytes, and supporting cells such as Sertoli and granulosa cells, potentially affecting gametogenesis and hormone regulation. At the cellular and subcellular levels, nanoparticle-induced oxidative stress, mitochondrial dysfunction, DNA damage, and epigenetic alterations may compromise gamete quality. At the embryonic level, exposure to nanomaterials during fertilization or early development raises concerns regarding embryotoxicity, including impaired cleavage, abnormal blastocyst formation, and altered implantation potential. In addition, certain nanomaterials may cross biological barriers, including the blood–testis barrier and placental barrier, thereby posing risks to fetal development. Importantly, the possibility of transgenerational effects should not be overlooked. Epigenetic modifications or genetic damage induced by nanomaterials may theoretically be transmitted to offspring, although current evidence remains limited and largely derived from animal studies. Taken together, future studies should incorporate systematic reproductive safety evaluation frameworks, including assessments of gamete integrity, embryo development, pregnancy outcomes, offspring health, and long-term follow-up. Establishing standardized testing protocols will be essential for advancing the safe application of nanotechnologies in reproductive medicine. In addition to biological challenges, the translation of nanotechnologies into clinical practice is also constrained by manufacturing and regulatory barriers. One major issue is the reproducibility of nanomaterials. Variations in particle size, surface charge, composition, and loading efficiency between batches can significantly influence biological performance and safety profiles. Scalable production under good manufacturing practice conditions remains difficult for many nanoplatforms, particularly for complex systems such as multifunctional nanoparticles and extracellular vesicles. Processes such as purification, sterilization, and storage may further alter nanoparticle properties, affecting stability and efficacy. Quality control is another critical challenge. Comprehensive characterization, including physicochemical properties, endotoxin levels, residual solvents, and degradation products, is required to ensure safety and consistency. For reproductive applications, additional considerations such as sterility, absence of reproductive toxicity, and compatibility with ART procedures are particularly important. Regulatory pathways for reproductive nanomedicine are also more stringent compared with many other therapeutic areas. Because these interventions may influence not only patients but also embryos and offspring, regulatory agencies are likely to require extensive preclinical data, including long-term reproductive toxicity and developmental studies. Future research in reproductive nanomedicine should move beyond proof-of-concept studies toward more standardized, mechanism-driven, and translationally oriented investigations. First, rational design of nanoplatforms based on structure–activity relationships, including particle size, surface functionalization, and controlled release behavior, will be essential for optimizing efficacy and safety. Second, more physiologically relevant models, including organoids and advanced in vitro reproductive systems, may help bridge the gap between animal studies and human applications. In addition to these advances, emerging biomimetic approaches inspired by natural antimicrobial systems are gaining increasing attention. In particular, antimicrobial peptides (AMPs), derived from innate host defense mechanisms, exhibit broad-spectrum antimicrobial activity, rapid bactericidal effects, and a relatively low propensity for inducing resistance. Recent advances have demonstrated that these peptides can be engineered or integrated with nanomaterials and biomaterial scaffolds to enhance their stability, targeting capability, and controlled release behavior. 177–179 Such hybrid systems combine the advantages of nanotechnology and peptide-based therapeutics, offering promising opportunities for addressing reproductive tract infections and inflammation. These developments suggest that AMP-inspired nanostructures may serve as a complementary direction to conventional nanoplatforms, further broadening the design space for next-generation reproductive nanomedicine. To facilitate clinical translation, well-designed preclinical studies with standardized outcome measures, followed by carefully controlled clinical trials, will be critical for evaluating therapeutic efficacy and safety. Particular emphasis should be placed on long-term reproductive outcomes and offspring health. Finally, interdisciplinary collaboration among materials scientists, reproductive biologists, clinicians, and regulatory experts will be crucial for accelerating the translation of nanotechnology from bench to bedside. While significant challenges remain, continued progress in nanomaterial design, safety evaluation, and manufacturing technologies is expected to gradually enable the integration of nanotechnology into clinical reproductive medicine.