Immunometabolism, the intersection of immune function and cellular metabolism, has emerged as a powerful lens for understanding and directing host response to biomaterials. Upon implantation, biomaterials often provoke immune activation, potentially leading to chronic inflammation, fibrotic encapsulation, and impaired integration. Recent advances point to sugar functionalization as a promising strategy to steer immunometabolic pathways, enhance biocompatibility, and promote regenerative outcomes. Naturally derived monosaccharides (e.g., mannose, glucose, galactose), polysaccharides (e.g., dextran, chitosan), and glycosaminoglycans (e.g., hyaluronic acid, heparin) engage distinct immune receptors to induce targeted metabolic reprogramming in macrophages, dendritic cells, and other innate effectors. This minireview synthesizes recent breakthroughs in the field, elucidating how distinct sugar classes reshape immunometabolism by modulating glycolysis, oxidative phosphorylation, fatty acid metabolism, and associated inflammatory pathways and highlighting their translational applications in precision medicine. We discuss design considerations for sugar-functionalized scaffolds and outline future directions centered on precision glycoengineering, integrated metabolic analyses, and personalized therapeutic platforms.

Valproic acid (VPA) is a potent antiseizure medication and mood stabilizer, yet its teratogenicity severely limits safe use during pregnancy. Despite guidelines advising against VPA use in women of reproductive age, it remains indispensable for certain drug-resistant epilepsies, highlighting the urgent need for safer and more targeted delivery strategies. Intranasal (IN) administration via nanocarriers represents a promising approach to enhance brain uptake while minimizing systemic exposure and placental transfer. In this review, we evaluate the scientific rationale and translational potential of IN nanoformulations of VPA specifically designed for use during pregnancy. We discuss strategies to engineer nanocarriers that achieve effective maternal brain delivery while reducing fetal risk, and we analyze preclinical data on biodistribution, placental passage, and therapeutic efficacy. Importantly, we highlight how gestational changes in maternal physiology and placental architecture can inform the rational design of pregnancy-adapted nanocarriers. By integrating insights from nanotechnology, pharmacology, and maternal-fetal medicine, this review outlines a paradigm shift from drug avoidance to precision delivery that maximizes reproductive safety. This strategy not only addresses the unmet need for safer VPA use in pregnancy, but also establishes a versatile framework for broader applications of nanomedicine in neurological and systemic disorders in women of childbearing age.

Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality and disproportionately affects Black women in the United States. While racial disparities in PTB are well documented, the molecular pathways underlying these differences remain incompletely understood. Extracellular vesicles (EVs) are circulating lipid-bound particles that carry coding and non-coding RNAs reflecting cellular stress states and may serve as integrative molecular indicators of pregnancy biology. In this hypothesis-generating pilot study, EVs were isolated from maternal plasma collected at delivery from non-Hispanic Black and non-Hispanic White women with preterm and full-term births. EV concentration and size were assessed, and EV-associated mRNA and miRNA cargo were profiled by next-generation sequencing (n = 5 per group), enabling differential expression and pathway enrichment analyses stratified by gestational outcome. EV concentrations were significantly elevated in PTB compared with full-term deliveries (p < 0.0001), with a greater increase among Black participants. Analysis of EV-associated mRNA transcripts identified a shared signature enriched for platelet activation and coagulation pathways across racial groups. Race-stratified analyses revealed distinct EV miRNA profiles in PTB, with enrichment of cytokine-mediated signaling pathways among Black participants and apoptosis-related pathways among White participants, while a subset of miRNAs differed by race independent of gestational outcome. These findings support EV profiling as a framework to investigate biological pathways contributing to PTB disparities.

Nanomedicine has progressed far beyond its early role as an experimental drug-carrier toolbox and today stands as a clinically validated enabling technology. Liposomal formulations and albumin-bound nanoparticles have transformed cancer therapy, while lipid nanoparticle (LNP) platforms accelerated the rapid development and global deployment of SARS-CoV-2 mRNA vaccines—demonstrating how nanoscale engineering can reshape therapeutic response, manufacturing speed, and public health impact. With these successes as foundation, the field is rapidly expanding into more sophisticated delivery systems including cell-hitchhiking nanoparticles, biomimetic multivalent vaccines, implantable immunotherapy depots, high-loading polymeric micelles, organ-targeted gene and RNA carriers, and bio-hybrid extracellular vesicle and mitochondrial therapies. These platforms aim not only to transport drugs, but to modulate immunity, direct regeneration, and enable precision intervention at the cellular and molecular scale. This perspective summarizes the current landscape of biomedical nanotechnologies and outlines how their continued evolution positions nanomedicine as an enabling science driving the next generation of therapeutics.

Abstract Neural tube closure relies on tightly coordinated morphogenetic programs integrating convergent extension, apical constriction of the neuroepithelium, and precise cell-cell interactions across germ layers. Disruption of these processes results in myelomeningocele, a severe complex congenital defect with lifelong multisystem consequences whose genetic and epigenetic determinants remain poorly defined. Using a sheep population with naturally occurring myelomeningocele, we quantified substantial heritability (0.42–0.68) and generated the first integrated multi-omics, multi-tissue atlas of this condition in any mammalian species. Genetic, transcriptomic, and whole-genome DNA methylation profiling across ectoderm- and mesoderm-derived tissues revealed shared and lineage-specific perturbations converging on cell-adhesion, cytoskeletal, migratory, inflammatory, and folate-responsive pathways. Chromosome 24 emerged as a multi-omics hotspot enriched for differentially expressed genes, differentially methylated regions, and candidate regulatory loci of GWAS signals, overlapping with human neurological and embryonic development trajectories. Cross-tissue network analyses highlighted coordinated disruption of neurulation-critical gene modules, establishing sheep as a robust translational model for mechanistic dissection of neural tube defect biology.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are emerging as potent cell-free mediators of tissue repair, whose composition and function can be tuned by the cellular microenvironment. Although inflammatory cues modulate mesenchymal stromal cell (MSC) behavior, how defined preconditioning strategies program extracellular vesicle (EV) functional outputs remains incompletely understood. Here, we systematically evaluated how priming bone marrow-derived MSCs with interferon-gamma/tumor necrosis factor-alpha (I/T) or lipopolysaccharide (LPS) generates EV populations with distinct immunomodulatory and regenerative properties. Using a murine full-thickness wound model, we performed an integrative analysis of biodistribution, immune response, and extracellular matrix (ECM) remodeling, complemented by single-cell, transcriptomic, and proteomic profiling. All EV populations were retained at the wound site following subcutaneous delivery and supported wound contraction; however, they drove distinct, treatment-specific repair trajectories. I/T-EVs promoted a coordinated regenerative response characterized by balanced macrophage (MΦ) activation, controlled immune modulation, and efficient resolution of inflammation, resulting in organized ECM remodeling. In contrast, LPS-EVs induced a more pro-inflammatory response, accelerating wound contraction and promoting compensatory matrix stiffening with reduced structural coordination. Control EVs primarily facilitated early immune resolution with limited induction of regenerative remodeling pathways. Proteomic profiling of EVs identified enrichment of proteins associated with insulin-like growth factor signaling, MΦ recruitment, and ECM remodeling, consistent with in vivo protein expression patterns and linking EV cargo to functional outcomes. These findings demonstrate that preconditioning does not uniformly enhance EV efficacy but instead selectively programs distinct MSC-EV functional states, establishing EV preconditioning as a tunable strategy for engineering cell-free therapeutics with predictable and context-specific therapeutic outcomes.

Several immunosuppressive therapies have been proposed as key treatment options for critically ill patients since the first appearance of severe acute respiratory syndrome coronavirus 2. Mesenchymal stem cells (MSCs) from different sources have been considered for their potential to attenuate the cytokine storm associated to COVID-19 and the consequent multi-organ failure, providing evidence for safe and efficacious treatments. Among them, administration of umbilical cord-derived MSCs (UC-MSCs) has demonstrated a significant increase in survival rates, largely due to their potent immunosuppressive properties. We applied next-generation sequencing (NGS) analysis to compare the transcriptomic profiles of MSCs isolated from two gestational sources: amniotic fluid (AF) obtained during prenatal diagnosis and their clinically relevant umbilical cord counterparts, for which datasets were publicly available. A full meta-analysis was performed to identify suitable GEO and NGS datasets for comparison between AF- and UC-MSC samples. Transcriptome analysis revelaed significant differences between groups, despite both cell lines being strongly involved in the tissue development, crucial to achieve the complex task of wound healing. Significantly enriched hallmark genes suggest AF-MSC superior immunomodulatory features against signaling pathways actively involved in the cytokine storm (i.e., IL-2/STAT, TNF-a/NFkB, IL-2/STAT5, PI3K/AKT/mTOR). The data presented here suggest that AF-MSCs hold significant promise for treating not only COVID-19-associated cytokine storms but also a variety of other inflammatory syndromes (i.e., those induced by bacterial infections, autoimmune disorders, and therapeutic interventions). Realizing the full potential of AF-MSCs as a comprehensive therapeutic approach in inflammatory disease management will require more extensive clinical trials and in-depth mechanistic studies.

Treating advanced ovarian cancer (OC) is challenging due to the immunosuppressive tumor microenvironment. This study investigates tumor-immune cell interactions using organotypic spheroid models that simulate the in vivo microenvironment. A dual-model spheroid system was established combining serous adenocarcinoma SKOV-3 cells with monocytes, pro-inflammatory (MΦ1) or anti-inflammatory (MΦ2) macrophages, or their derived exosomes (EXOs). In Model A, immune cells or EXOs were co-seeded with tumor cells to replicate early heterotypic aggregation. In Model B, immune cells or EXOs were introduced 24 h post-spheroid formation to simulate immune infiltration into established spheroids. Spheroid morphology was quantified by diameter and circularity, while the distribution of immune cells and EXOs was assessed via fluorescence intensity profiling in 2D and 3D. epithelial-to-mesenchymal transition (EMT) marker expression was analyzed to assess tumor cell phenotypic changes. Spheroids formed with SKOV-3 cells and ThP-1 monocytes developed a dense monocyte-enriched outer layer. Macrophage subtypes differentially influenced spheroid morphology: MΦ2 macrophages promoted the formation of multiple, loosely organized spheroids and increased N-cadherin expression, indicative of enhanced EMT. Similarly, MΦ-EXOs modulated EMT marker expression, underscoring the contribution of both direct cell interactions and paracrine signaling in regulating spheroid dynamics. Macrophages and their exosomes play a critical role in modulating the architecture and functional behavior of spheroids, reflecting two key aspects of OC progression: the formation of immune cell-enriched spheroids in ascitic fluid and tumor-immune interactions at peritoneal metastatic sites. This model provides a clinically relevant platform for preclinical testing of therapeutic strategies targeting peritoneal dissemination in OC.

Small alterations during the early stages of the innate immune response to an implant can drive large changes in adaptive immunity. Biomaterials for regenerative purposes can be engineered to modulate this immune response in beneficial ways. This study presents an innovative patch designed and functionalized to target the innate immunity at the implant site. Mannose moieties are incorporated into collagen patches, resulting in a technology called Local Immunotuning Patch (LIP), designed to directly interact with antigen presenting cells through their mannose receptor. In vitro, LIP shows anti-inflammatory effects on bone marrow-derived macrophages and inhibitory properties even on methicillin-resistant bacterial strains. Subcutaneous implantation in mice reveals that LIP modulates multiple pathways related to innate and adaptive immunity, underscoring its role in shaping an immune-engineered environment around the implant. These findings highlight the potential of this strategy to control the foreign body reaction at the implant site, making it applicable for various uses, including wound healing and surgical infection control in reconstructive procedures.

Background Mesenchymal stem cells (MSCs) from gestational tissues represent promising strategies for in utero treatment of congenital malformations, but plasticity and required high-risk surgical procedures limit their use. Here we propose natural exosomes (EXOs) isolated from amniotic fluid-MSCs (AF-MSCs), and their mimetic counterparts (MIMs), as valid, stable, and minimally invasive therapeutic alternatives. Methods MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. Physiochemical and molecular characterization was performed to compare them to EXOs released from the same number of cells. The possibility to exploit both formulations as mRNA-therapeutics was explored by evaluating cell uptake (using two different cell types, fibroblasts, and macrophages) and mRNA functionality overtime in an in vitro experimental setting as well as in an ex vivo, whole embryo culture using pregnant C57BL6 dams. Results Molecular and physiochemical characterization showed no differences between EXOs and MIMs, with MIMs determining a 3-fold greater yield. MIMs delivered a more intense and prolonged expression of mRNA encoding for green fluorescent protein (GFP) in macrophages and fibroblasts. An ex-vivo whole embryo culture demonstrated that MIMs mainly accumulate at the level of the yolk sac, while EXOs reach the embryo. Conclusions The present data confirms the potential application of EXOs for the prenatal repair of neural tube defects and proposes MIMs as prospective vehicles to prevent congenital malformations caused by in utero exposure to drugs.

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties involved in target cell regulation, tissue homeostasis, and cancer cell inhibition through the highlighted Wnt, TNF, and TGF-β signaling pathways. Transcriptomic data were experimentally confirmed through in vitro assays, by evaluating the anti-cancer effect of the media conditioned by AF- and CV-MSCs and the exosomes derived from them on ovarian cancer cells, revealing inhibitory effects in 2D (by reducing cell viability and inducing apoptosis) and in 3D conditions (by negatively interfering with spheroid formation). These data provide molecular insights into the potential role of gestational tissues-derived MSCs as source of anti-cancer factors, paving the way for the development of therapeutics to create a pro-regenerative environment for tissue restoration following injury, disease, or against degenerative disorders.

Purpose of Review Spina bifida (SB) is a severe birth defect that affects 1400 newborns annually in the USA. SB is often diagnosed before irreversible neurological damage occurs, making it possible to exploit the therapeutic potential of mesenchymal stem cell (MSC)-based therapeutics as intervention strategies for neural tissue protection against further damage. Here, we discuss the most recent MSC-based intervention strategies developed to create an in utero pro-regenerative environment. Recent Findings MSCs show potential benefits in the prenatal treatment of SB due to their remarkable healing and protective potential, both in preclinical and clinical studies. While promising, current in utero tissue repair strategies remain highly invasive for the mother and the fetus Summary We provide insights on the mechanisms activated by MSCs in utero and discuss the advantages of MSC-free approaches, as minimally invasive tools capable of functional tissue repair while reducing the limitations of current therapeutics.

This concise review delves into the pivotal role of three-dimensional (3D) nanostructured scaffolds in fostering mesenchymal stromal cells (MSC) immunomodulatory capabilities, with a specific focus on orthopedic applications. In this ever-advancing research field, where inflammation and tissue repair are intricately linked, manipulation of the immunomodulatory properties of MSCs becomes crucial, especially for inflammatory-based diseases such as osteoarthritis (OA). The primary inquiries include the promise of nanoscale tools to revolutionize orthopedic regenerative medicine, the role of tailored design features in steering cellular immunomodulatory response, and the resulting beneficial impact on tissue regeneration. Recent studies demonstrate the crucial importance of precise control over 3D scaffold design at the nanoscale to maximize the efficacy of regenerative therapies. Compared to 2D, engineered 3D environments with specific chemical composition and finely tuned physical nano-features, heighten MSC secretion of immunosuppressive factors including transforming growth factor-β1 (TGF-β1), prostaglandin E2 (PGE2), indoleamine-pyrrole 2,3-dioxygenase (IDO), and interleukin-10 (IL-10), contributing to improve cartilage and osteo differentiation. Nanostructured 3D scaffolds characterized by nano topography, roughness, high porosity, biomimetic stiffness and chemistry, offer a sophisticated means to optimize the immunosuppressive potential of MSCs by allowing the spatiotemporal control over signaling molecules at the nanoscale. Polymeric constructs, notably collagen-based ones, lead to heightened immunomodulatory response and superior cellular differentiation. This effect is because 3D constructs provide a biomimetic environment that enhances cell interaction, controls cell behavior, and modulates the secretion of anti-inflammatory cytokines. The integration of innovative 3D nanostructured approaches into MSC culture systems paves the way for significant strides in cell therapy, addressing current challenges in their clinical application and holding great promise for developing more effective and precise treatments for orthopedic inflammatory disorders.

Background Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity. Methods Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were carried out to confirm the biological processes identified as enriched in DS-CV compared to CV (i.e., cell cycle, proliferation features, immunosuppression and ROS production). Results Genes located on chromosomes other than the canonical 21 (Ch. 2, 6 and 22) are responsible for the impairment of life-essential pathways, including cell cycle regulation, innate immune response and reaction to external stimuli were found to be differentially expressed in DS-CV. Experimental validation confirmed the key role of the biological pathways regulated by those genes in the etiology of such a multisystem condition. Conclusions NGS dataset generated in this study highlights the compromised functionality in the proliferative rate and in the innate response of DS-associated clinical conditions and identifies DS-CV as suitable tools for the development of specifically tailored, personalized intervention modalities.

Millions of women give birth every year worldwide [...]

Nanotechnology, the art of engineering structures on a molecular level, offers the opportunity to implement new strategies for the diagnosis and management of pregnancy-related disorders. This review aims to summarize the current state of nanotechnology in obstetrics and cancer in pregnancy, focusing on existing and potential applications, and provides insights on safety and future directions. A systematic and comprehensive literature assessment was performed, querying the following databases: PubMed/Medline, Scopus, and Endbase. The databases were searched from their inception to 22 March 2022. Five independent reviewers screened the items and extracted those which were more pertinent within the scope of this review. Although nanotechnology has been on the bench for many years, most of the studies in obstetrics are preclinical. Ongoing research spans from the development of diagnostic tools, including optimized strategies to selectively confine contrast agents in the maternal bloodstream and approaches to improve diagnostics tests to be used in obstetrics, to the synthesis of innovative delivery nanosystems for therapeutic interventions. Using nanotechnology to achieve spatial and temporal control over the delivery of therapeutic agents (e.g., commonly used drugs, more recently defined formulations, or gene therapy-based approaches) offers significant advantages, including the possibility to target specific cells/tissues of interest (e.g., the maternal bloodstream, uterus wall, or fetal compartment). This characteristic of nanotechnology-driven therapy reduces side effects and the amount of therapeutic agent used. However, nanotoxicology appears to be a significant obstacle to adopting these technologies in clinical therapeutic praxis. Further research is needed in order to improve these techniques, as they have tremendous potential to improve the accuracy of the tests applied in clinical praxis. This review showed the increasing interest in nanotechnology applications in obstetrics disorders and pregnancy-related pathologies to improve the diagnostic algorithms, monitor pregnancy-related diseases, and implement new treatment strategies.