Nanomedicine for Women's Health

The field of medicine known as “Women's Health” focuses on diagnosing and treating diseases and disorders affecting a woman's physical and mental well-being. Women face unique health issues and conditions, including but not limited to pregnancy complications, menopause, gynecological disorders, and malignancies. The Eunice Kennedy Shriver National Institute of Child Health and Human Development also indicated that while both men and women share certain health issues, they are affected differently. For instance, breast cancer, osteoarthritis, and urine incontinence are more prevalent in women. In addition, women are more likely to die after a heart attack. Consequently, therapeutic and diagnostic strategies must be meticulously designed for women's health issues. The available literature indicates that nanotechnology is a promising strategy for developing of effective and personalized treatment modalities for various diseases, and it has the potential to revolutionize women's health in several key areas. For instance, it enables the development of targeted drug delivery systems that can enhance the efficacy of treatments while minimizing side effects. This is particularly crucial in treating diseases such as gynecological cancers and endometriosis, where precision in targeting disease cells can significantly improve patient outcomes. Furthermore, nanomedicine holds promise in the realm of female reproductive health. Nanoparticles can be used to deliver various therapeutic agents to specific sites within the reproductive system, offering new treatment options for conditions such as infertility, polycystic ovary syndrome, and others. Furthermore, nanotechnology-enabled imaging techniques can provide more precise and earlier detection of gynecological diseases, allowing for timely intervention and better management of these conditions. Finally, nanomedicine has significant potential in addressing pregnancy complications and enhancing maternal and fetal health. For instance, nanoparticles can be designed to accumulate in the implantation site, enabling targeted delivery of drugs or imaging agents to the placenta or fetus. This could be crucial for diagnosing and treating conditions like ectopic pregnancy, preeclampsia, or fetal growth restriction. This special issue on “Nanomedicine for Women's Health” presents a comprehensive collection of twenty papers (1 Perspective, 4 Research articles, and 15 Reviews) highlighting the transformative potential of nanotechnology in women's healthcare. The papers collectively cover a broad spectrum of innovative therapeutic and diagnostic approaches, showcasing the versatility and efficacy of nanomedicine across various health conditions and diseases that primarily affect women. A substantial number of published articles have reported on the application of innovative nanomedicine platforms for treating and imaging gynecological and breast cancers. For instance, Garbuzenko et al. introduced an advanced nanotechnology-based strategy for the personalized treatment of ovarian carcinoma, meticulously tailored to the individual genetic profile of the patient's tumor.[1] By employing targeted nanoparticle-based delivery systems loaded with the most effective siRNA and anticancer agents selected for each individual patient, they demonstrated that these personalized treatment protocols significantly suppress drug resistance, inhibit tumor progression, and prevent the development of metastases while mitigating the adverse side effects typically associated with conventional therapies. In another study, Naguib et al. developed an innovative therapeutic approach for type II endometrial cancer utilizing polymeric nanoparticles loaded with CIP2b, a novel derivative of the fluoroquinolone antibiotic ciprofloxacin.[2] Animal studies demonstrated that CIP2b-loaded nanoparticles, when administered in combination with paclitaxel, significantly reduced tumor growth without causing any apparent off-target toxicity. This special issue also includes a series of comprehensive review papers that delve into various aspects of nanomedicines for female cancers, providing readers with critical insights and a thorough understanding of the latest advancements, challenges, and future directions in this rapidly evolving field. Liu et al. critically examined recent advancements in nanomedicine aimed at enhancing mucosal penetration and therapeutic efficacy of therapeutic agents for treating cervical cancer.[3] By discussing the physiological characteristics of the cervicovaginal environment, the authors delve into both “mucus-adhering” and “mucus-penetrating” strategies, showcasing their mechanisms, applications, and effectiveness. Additionally, the review highlights the challenges and future directions in the rational design and synthesis of nanomedicine for localized cervical cancer therapy. In another article, Korzun et al. comprehensively explored the latest advancements in nucleic acid-based nanomedicines designed for the treatment of gynecological malignancies.[4] By highlighting the potential of microRNA, small siRNA, and mRNA therapeutics, the authors emphasize innovative approaches to overcoming chemotherapy resistance and improving therapeutic outcomes. The review also discusses current preclinical studies and their implications for future clinical applications. In this special issue, Nevins et al. discussed cutting-edge nanotechnology strategies for mitigating the adverse side effects of chemotherapy, such as neurotoxicity, neuropathy, and cardiomyopathy, which significantly impact the quality of life of cancer survivors.[5] The authors highlight innovative solutions to enhance therapeutic efficacy and reduce off-target toxicity by detailing current nanomaterial approaches for targeted drug delivery and controlled release. This special issue includes a series of comprehensive reviews that highlight the application of nanomedicine for breast cancer. For instance, Ashkarran et al. present recent advances in nanotechnology for the early detection and treatment of metastatic breast cancer.[6] The review emphasizes the potential of nanomedicine to improve the identification of metastatic cells before they spread, allowing for timely and more effective therapeutic interventions. It also explores how nanoparticle-based platforms can enhance drug delivery, reduce drug resistance, and minimize side effects, thereby improving patient outcomes in metastatic breast cancer. Wang et al. examine innovative nanotechnology applications in breast cancer immunotherapy.[7] They detail how nanoparticles can be engineered to boost the immune system's response against cancer cells, offering targeted treatment options that enhance the efficacy of immunotherapies. The authors discuss various nanoparticle formulations designed to improve antigen delivery, modulate immune checkpoints, and stimulate immune cells, providing a comprehensive overview of how nanomedicine can transform breast cancer immunotherapy. Additionally, Torres Quintas et al. thoroughly review emerging nanotechnologies for treating triple-negative breast cancer.[8] This article addresses the challenges associated with treating this aggressive breast cancer subtype and highlights novel therapeutic approaches that leverage the unique properties of nanomaterials. The authors discuss the development of multifunctional nanoparticles that can deliver chemotherapeutic agents, enhance imaging for better tumor localization, and provide combined therapy options to improve treatment efficacy and patient prognosis. Importantly, this special issue also includes a crucial review by Rowlands et al., which addresses the stark racial disparities in endometrial cancer outcomes, particularly highlighting the higher mortality rates among Black women compared to their White counterparts.[9] The authors explore how systemic and interpersonal racism contribute to these disparities and discuss the potential of nanomedicine to bridge this gap. By leveraging nanoparticle-based therapeutics, the review emphasizes the role of precision medicine in improving diagnosis and treatment tailored to patients' genetic profiles. This approach aims to enhance therapeutic efficacy, mitigate the adverse effects, and improve access to care for underserved populations. Given the rising incidence and mortality rates of endometrial cancer, this review underscores the urgent need for innovative solutions to address health inequities. It provides a comprehensive analysis of how nanotechnology can play a pivotal role in achieving this goal. This special issue also features several papers on the innovative applications of nanomedicine to enhance maternal and fetal health. Carter et al. highlight how nanotechnology can provide groundbreaking solutions for managing infertility, obstetric complications, and fetal conditions.[10] The authors specifically discuss the influence of the menstrual cycle and pregnancy on nanoparticle distribution, showcasing the effectiveness of nanomedicine in targeting the placenta and fetus. Complementing Carter's work, Stapleton et al. explore the application of engineered nanomaterials in perinatal therapeutics, addressing pre-existing maternal conditions, pregnancy disorders, placental pathologies, and fetal concerns that may require targeted diagnostics or treatments.[11] The authors also pay significant attention to the in vitro and in vivo models used to study perinatal nanomedicine and highlight the importance of comprehensive toxicological assessments to identify and mitigate any risks associated with using nanomaterials in pregnant patients. In another review, Geisler et al. specifically focus on advanced nanomedicine strategies for managing placental disorders such as preeclampsia, fetal growth restriction, placenta accreta spectrum, and gestational trophoblastic disease.[12] This article provides detailed insights into the pathophysiology of these placental disorders, identifying novel disease targets that could inspire the rational design of precision nanocarriers capable of selectively targeting the placenta while protecting the fetus. Deepak et al. further enhance this discussion by presenting innovative strategies for drug delivery to the placenta aimed to treat preeclampsia and fetal growth restriction.[13] They emphasize the significance of developing targeted therapies that can accumulate specifically in the placenta and deliver drugs efficiently without harming the fetus. This review underscores the complexity and importance of understanding placental biology to advance therapeutic options for these critical conditions. Furthermore, the research article by Mamnoon et al. introduces novel nanoparticle-based drug carriers, known as polymersomes, which preferentially accumulate in the placenta following systemic administration without reaching the fetus.[14] The authors demonstrated that these polymersomes could be efficiently loaded with methotrexate, significantly improving the management of ectopic pregnancy, a condition characterized by the abnormal implantation of an embryo outside the uterus. The polymersomes contain a disulfide bond that responds to the high intracellular concentrations of glutathione within placental cells, causing the nanocarriers to disintegrate and rapidly release the drug. Animal studies show that these polymersomes significantly enhance the therapeutic efficacy of methotrexate, inducing pregnancy demise at a much lower dose compared to the free drug. Additionally, the research highlights the safety and biocompatibility of the developed polymersomes, as mice treated with methotrexate-loaded polymersomes were able to conceive and give birth to healthy pups following treatment. The comprehensive review by Moses et al. complements this work by discussing the potential of nanomaterials to improve both the diagnosis and treatment of ectopic pregnancy.[15] The authors highlight various nanotechnology-based approaches, including the use of nanoparticles for the targeted delivery of imaging agents and therapeutics to the implantation site. The review also emphasizes the importance of developing sensitive and specific biomarkers, as well as advanced imaging techniques like photoacoustic and fluorescence imaging, to enhance the early detection and accurate localization of ectopic pregnancies. Additionally, the authors explore the therapeutic potential of nanomedicines, such as the targeted delivery of methotrexate using lipid-polymer nanoparticles, to increase efficacy and reduce systemic side effects. In this special issue, readers will discover two review articles that highlight the transformative potential of RNA therapy during pregnancy, emphasizing both its significant promise and the challenges that need to be addressed. Thus, Chaudhary et al. discuss the use of RNA therapeutics for various prenatal applications, including gene therapy, protein replacement, maternal vaccination, and fetal gene editing.[16] They explore the current landscape of RNA (siRNA and mRNA) therapeutics and non-viral delivery platforms, which are actively being developed for safe administration during pregnancy. The authors emphasize advancements in RNA drugs specifically designed to combat pregnancy-related conditions such as preeclampsia and infectious diseases like SARS-CoV-2 and Zika virus during pregnancy. They also highlight the critical need for accurate cell-based and animal models that mimic the maternal-fetal interface to better study the efficacy and safety of these RNA therapies. In another insightful article, Safford et al. investigate the engineering of lipid nanoparticles (LNPs) for efficient mRNA delivery to the placenta, addressing pregnancy-related disorders such as preeclampsia and fetal growth restriction.[17] Utilizing an orthogonal design of experiments, they screen and optimize LNP formulations, identifying a lead candidate, LNP C5, which demonstrates a fourfold increase in mRNA delivery in vitro and significant improvement in vivo delivery to placental cells compared to standard formulations. This study highlights the potential of tailored LNPs for targeted mRNA therapy, emphasizing the importance of precise excipient optimization to enhance therapeutic outcomes while minimizing cytotoxicity. Aside from the above articles, Luo et al. highlight how nanotechnology can revolutionize the diagnosis and treatment of gynecological conditions, including gynecological cancers, as well as endometriosis and pelvic inflammatory disease.[18] They discuss the use of nanoparticles in magnetic resonance imaging, where iron oxide nanoparticles provide higher contrast and better resolution. Similarly, applying nanoparticles in computed tomography and ultrasound improves image clarity, while photoacoustic and fluorescence imaging offer high-resolution, real-time visualization of tissues and lesions using nanoparticles. Luo et al. also highlight the potential of multimodal imaging, which combines multiple imaging techniques to provide comprehensive diagnostic information and enable better monitoring of biological processes in real time. On the therapeutic front, the review explores the therapeutic applications of photodynamic therapy and photothermal therapy using nanoparticles, which offer promising, non-invasive treatment options for gynecological conditions. In addition to this review, Barth et al. present the development and evaluation of a near-infrared fluorescent nerve-specific contrast agent, LGW08-35, designed to enhance nerve-sparing techniques during gynecological surgeries.[19] This agent aims to address the high incidence of nerve damage that occurs during procedures like hysterectomy and cystectomy, which can result in significant long-term side effects such as urinary and fecal incontinence and sexual dysfunction. The authors formulate LGW08-35 using a micelle-based approach to improve its solubility and stability for clinical use. The study demonstrates that LGW08-35 selectively highlights the femoral, sciatic, lumbar, iliac, and hypogastric nerves in both rodent and swine models. This fluorescence-guided surgery technique allows for real-time, high-contrast visualization of nerves, facilitating nerve-sparing efforts and potentially reducing surgical complications. Finally, the perspective by Lin et al. complements the overall theme of the special issue by highlighting the crucial influence of sex-specific differences on the safety and therapeutic efficacy of cardiac nanomedicines.[20] The authors emphasize the differences in cardiovascular health between males and females, including disparities in heart structure, function, and molecular composition, which can influence the interaction and effectiveness of nanomedicines. These differences can significantly impact how nanomedicines interact with cardiac tissues and their overall effectiveness. Lin et al. stress the necessity of incorporating sex as a biological variable in the development and implementation of nanomedicine strategies for cardiovascular diseases. This approach is essential to developing more effective and safer nanomedicine therapies tailored to the unique needs of both sexes. As we conclude this special issue, we would like to extend our deepest gratitude to all the contributing authors for their outstanding research and insightful reviews. Their dedication and innovative approaches have significantly enriched our understanding of how nanomedicine can transform women's health and address critical maternal and fetal care challenges. We would also like to acknowledge and thank the deputy editor of Small, Dr. Ekaterina Perets, for her vision and leadership in initiating and running this special issue. Her commitment to advancing the field of nanomedicine for women's health has been instrumental in bringing together this collection of pioneering work. Finally, we thank the reviewers for their thorough and constructive feedback, which has helped to ensure the high quality of the articles published in this issue. We hope the findings and perspectives presented here will inspire further research and collaboration, ultimately leading to improved health outcomes for women worldwide. This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD101450), the National Cancer Institute of the National Institutes of Health (R01CA237569, R01CA269513 and R37CA234006), and the College of Pharmacy at Oregon State University. The authors declare no conflict of interest. Tamara Minko is a Distinguished Professor and Chair of the Department of Pharmaceutics at Ernest Mario School of Pharmacy. Her research interests include biopharmaceutics; nanoscale-based targeted delivery of therapeutic agents; translational and personalized medicine, etc. She is an author of over 400 publications. Dr. Minko is an Elected Fellow of American Association of Pharmaceutical Scientists, Controlled Release Society, American Institute for Medical and Biological Engineering, and International Association of Advanced Materials, Past President of Controlled Release Society, Executive Editor of Advanced Drug Delivery Reviews, Editor of Pharmaceutical Research, member of Editorial Board of ten scientific journals, Study Sections at NIH and other review panels. Oleh Taratula received his Ph.D. in chemistry from Rutgers, The State University of New Jersey, in 2008. In 2011, he completed his postdoctoral research training at the Ernest Mario School of Pharmacy under the supervision of Dr. Tamara Minko. Currently, Dr. Taratula is a Professor of Pharmaceutics at the College of Pharmacy at Oregon State University and a co-director of the Center for Innovative Drug Delivery and Imaging. His primary research focus is the development of multifunctional nanoplatforms for imaging and the specific eradication of cancer, endometriosis, and other diseases.