Search Results (984)

Pulmonary fibrosis (PF) is a group of chronic progressive lung diseases characterized by irreversible remodeling of lung tissue structure, abnormal proliferation of fibroblasts, and excessive deposition of extracellular matrix (ECM), among which idiopathic pulmonary fibrosis (IPF) is the most typical subtype. Currently, the only two clinically approved therapeutic drugs (nintedanib and pirfenidone) can only partially slow disease progression without reversing fibrotic lesions, and are associated with varying degrees of adverse effects. Oxidative stress, defined as a pathological imbalance between systemic oxidant and antioxidant systems, has been substantiated by extensive research as a pivotal mechanism driving the pathogenesis and progression of pulmonary fibrosis. This review summarizes the regulatory mechanisms of oxidative stress in pulmonary fibrosis, with a focus on its critical role in inducing and promoting fibrosis through relevant target cells and signaling pathways. We also specifically highlight the latest progress and challenges in therapeutic strategies targeting oxidative stress, and discuss next-generation therapies, including the modulation of endogenous antioxidant pathways, supplementation of exogenous antioxidants, as well as nanomaterials, exosomes, and combination therapies. We hope this review will deepen the understanding of oxidative stress and pulmonary fibrosis, and provide new directions for improving the clinical efficacy of oxidative stress-targeted therapies. Full article

Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal role in endothelial cell proliferation, migration, survival by anti-apoptotic signaling, and vascular permeability. Dysregulation of VEGFA is closely linked to pathological neovascularization. Exosomes, nanosized phospholipid bilayer vesicles ranging from 30 to 150 nm, have emerged as promising gene delivery vehicles due to their intrinsic low immunogenicity, superior cellular uptake, and enhanced in vivo stability. This study aimed to investigate whether highly purified mesenchymal stem cell (MSC)-derived exosomes loaded with VEGFA siRNA labeled with FAM can effectively suppress pathological corneal neovascularization (CNV) via targeeted cellular transduction and VEGFA inhibition. Furthermore, we examined whether the therapeutic effect involves the modulation of the PI3K–Akt–Caspase-3 signaling axis. Methods: Exosomes purified by chromatography were characterized by electronmicroscopy, standard marker immunoblotting, and nanoparticle tracking analysis. In vitro, we assessed exosome uptake and cytoplasmic release, suppression of VEGFA mRNA/protein, cell viability, and apoptosis. In a mouse CNV model, we evaluated tissue reach and stromal retention after repeated intrastromal injections; anterior segment angiogenic indices; CD31/VEGFA immunofluorescence/immunoblotting; phosphorylated PI3K and Akt; cleaved caspase-3; histology (H&E); and systemic safety (liver, kidney, and spleen). Results: Exosomes were of high quality and showed peak efficacy at 48 h, with decreased VEGFA mRNA/protein, reduced viability, and increased apoptosis in vitro. In vivo, efficient delivery and stromal retention were observed, with accelerated inhibition of neovascularization after Day 14 and maximal effect on Days 17–19. Treatment reduced CD31 and VEGFA, decreased p-PI3K and p-Akt, and increased cleaved caspase-3. Histologically, concurrent reductions in neovascularization, inflammatory cell infiltration, and inflammatory epithelial thickening were observed, alongside a favorable systemic safety profile. Conclusions:VEGFA siRNA-loaded exosomes effectively reduce pathological CNV via a causal sequence of intracellular uptake, cytoplasmic release, targeted inhibition, and phenotypic suppression. Supported by consistent PI3K–Akt inhibition and caspase-3–mediated apoptosis induction, these exosomes represent a promising local gene therapy that can complement existing antibody-based treatments. Full article

Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9⁺/Fgfr3⁺ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1⁺ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5⁺ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a–Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh–PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint. Full article

Background: Organ transplant offers patients a second chance at life, yet chronic rejection remains a formidable barrier to long-term success. Unlike the instantaneous storm of acute rejection, chronic rejection is a slow, unremitting process that silently remodels vessels, scars tissues, and diminishes graft function. At the center of this process are macrophages, immune “shapeshifters” that can heal or harm depending on their cues. Methods: This manuscript systematically reviews and synthesizes the current evidence from experimental studies and clinical observations, as well as molecular insights, to unravel how macrophages orchestrate chronic rejection. It travels over macrophage origins alongside their dynamic polarization into pro-inflammatory (M1) or pro-repair yet fibrotic (M2) states. The discussion integrates mechanisms of recruitment, antigen presentation, vascular injury, and fibrosis, while highlighting the molecular pathways (NF-κB, inflammasomes, STAT signaling, metabolic rewiring) that shape macrophage fate. Results: Macrophages play a central role in chronic rejection. Resident macrophages, once tissue peacekeepers, amplify inflammation, while recruited monocyte-derived macrophages fuel acute injury or dysfunctional repair. Together, they initiate transplant vasculopathy through cytokines, growth factors, and matrix metalloproteinases, slowly narrowing vessels and starving grafts. Donor-derived macrophages, often overlooked, act as early sentinels and long-term architects of fibrosis, blurring the line between donor and host immunity. At the molecular level, macrophages lock into destructive programs, perpetuating a cycle of inflammation, vascular remodeling, and scarring. Conclusions: Macrophages are not passive bystanders but pivotal decision makers in chronic rejection. Their plasticity, while a source of pathology, also opens therapeutic opportunities. Emerging strategies like macrophage-targeted drugs, immune tolerance approaches, gene and exosome therapies currently offer ways to reprogram these cells and preserve graft function. By shifting the macrophage narrative from saboteurs to guardians, transplantation medicine may transform chronic rejection from an inevitability into a preventable complication, extending graft survival from fleeting years into enduring decades. Full article

Objective: Diabetic kidney disease (DKD) is characterized by podocyte injury and impaired autophagy. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) exhibit therapeutic potential for DKD, yet their mechanisms remain unclear. This study investigated whether BMSC-Exos restore podocyte autophagy via the miR-143-3p/Bcl-2/Beclin1 axis to delay DKD progression. Methods: A high-glucose (HG)-induced podocyte injury model was established using mouse podocytes (MPC5). Autophagy-related proteins (Beclin1, Bcl-2, LC3) and the injury marker desmin were analyzed by Western blot and immunofluorescence (IF). High-throughput sequencing identified BMSC-Exos-enriched miRNAs, with the miR-143-3p/Bcl-2 targeting relationship validated by dual-luciferase reporter assays. BMSCs transfected with miR-143-3p mimic or inhibitor were used to assess exosomes effects on autophagy and podocin expression. In vivo, DKD mice received tail vein injections of modified BMSC-Exos, followed by evaluation of physiological parameters, biochemical indices, and renal histopathology. Results: BMSC-Exos were successfully isolated and characterized. Fluorescence microscopy confirmed exosomes internalization by HG-treated MPC5 cells. BMSC-Exos upregulated Beclin1 and LC3-II while downregulating Bcl-2 and desmin, indicating enhanced autophagy. High-throughput sequencing revealed miR-143-3p enrichment in BMSC-Exos, and Bcl-2 was confirmed as a direct target of miR-143-3p. Exosomes from miR-143-3p mimic-transfected BMSCs further promoted autophagy and podocin expression. In DKD mice, BMSC-Exos reduced blood glucose, urinary albumin-to-creatinine ratio (UACR), and ameliorated renal damage, whereas miR-143-3p inhibition attenuated these effects. Conclusions: BMSC-Exos deliver miR-143-3p to target Bcl-2, thereby activating Beclin1-mediated autophagy and ameliorating DKD. This study elucidates a novel autophagy regulatory mechanism supporting BMSC-Exos as a cell-free therapy for DKD. Full article

Acute lung injury (ALI) is in part precipitated by hyperbaric oxygen or other mechanical insults. It constitutes the fundamental pathological process underlying acute respiratory distress syndrome (ARDS). The manifestation of the condition is characterized by an uncontrolled inflammatory response and alveolar edema, consequent to the disruption of the alveolar–capillary barrier. This phenomenon is associated with elevated morbidity and mortality rates. The current therapeutic interventions for ALI are not well researched or articulated. However, recent studies have indicated that stem cells may possess therapeutic potential in the context of ALI. The present study demonstrates that these exosome preparations have the capacity to significantly ameliorate radiographic findings, histological parameters, and vascular permeability in murine models of ALI. Concurrently, they attenuate the inflammatory response to a certain extent. The present review commences with an examination of the pathogenic mechanisms and manifestations of pulmonary injury induced by hyperbaric oxygen or other external factors. The subsequent sections of the text provide detailed accounts of the latest advances in exosome-based therapies for mitigating such injury, including their mechanisms of action and future translational prospects. While exosome-based treatments have demonstrated considerable advancement in preclinical research, numerous challenges must be surmounted before their widespread implementation in clinical settings can be realized, underscoring the necessity for sustained research in this domain. Full article

Hair loss disorders, particularly androgenetic alopecia (AGA), are common conditions that carry significant psychosocial impact. Current standard therapies, including minoxidil, finasteride, and hair transplantation, primarily slow progression or re-distribute existing follicles and do not regenerate lost follicular structures. In recent years, regenerative medicine has been associated with a gradual shift toward approaches that aim to restore follicular function and architecture. Stem cell-derived conditioned media and exosomes have shown the ability to activate Wnt/β-catenin signaling, enhance angiogenesis, modulate inflammation, and promote dermal papilla cell survival, resulting in improved hair density and shaft thickness with favorable safety profiles. Autologous cell-based therapies, including adipose-derived stem cells and dermal sheath cup cells, have demonstrated the potential to rescue miniaturized follicles, although durability and standardization remain challenges. Adjunctive interventions such as microneedling and platelet-rich plasma (PRP) further augment follicular regeneration by inducing controlled micro-injury and releasing growth and neurotrophic factors. In parallel, machine learning-based diagnostic tools and deep hair phenotyping offer improved severity scoring, treatment monitoring, and personalized therapeutic planning, while robotic Follicular Unit Excision (FUE) platforms enhance surgical precision and graft preservation. Advances in tissue engineering and 3D follicle organoid culture suggest progress toward producing transplantable follicle units, though large-scale clinical translation is still in early development. Collectively, these emerging biological and technological strategies indicate movement beyond symptomatic management toward more targeted, multimodal approaches. Future progress will depend on standardized protocols, regulatory clarity, and long-term clinical trials to define which regenerative approaches can reliably achieve sustainable follicle renewal in routine cosmetic dermatology practice. Full article

Spina bifida (SB) is a congenital malformation of the central nervous system (CNS), resulting from incomplete closure of the neural tube (NT) during early embryogenesis. Myelomeningocele (MMC), the most severe form of SB, leads to progressive neurological, orthopedic, and urological dysfunctions due to both NT developmental failure and secondary intrauterine injury (“two-hit hypothesis”). Prenatal repair of MMC has progressed considerably since the Management of Myelomeningocele Study (MOMS, 2011) trial, which showed that open fetal surgery can decrease the need for shunting and improve motor function, although it carries significant maternal risks. To address these limitations, minimally invasive techniques have been developed, with the goal of achieving similar benefits for the fetus while reducing maternal morbidity. Recent research has shifted toward regenerative strategies, integrating mesenchymal stem cells (MSCs), bioengineered scaffolds, and cell-derived products to move beyond mere mechanical protection toward true NT repair. Preclinical studies in rodent and ovine models have shown that amniotic- and placenta-derived MSCs exert neuroprotective and immunomodulatory paracrine effects, promoting angiogenesis, modulating inflammation, and supporting tissue regeneration. Minimally invasive, cell-based interventions such as Transamniotic Stem Cell Therapy (TRASCET), in preclinical rodent models, offer the possibility of very early treatment without hysterotomy, although translation remains limited by the lack of large-animal validation and long-term safety data. In parallel, advances in biomaterials, nanostructured scaffolds, and exosome-based therapies reinforce a regenerative paradigm that may improve neurological outcomes and quality of life in affected children. Ongoing translational studies are essential to optimize these approaches and define their safety and efficacy in clinical settings. This review provides an integrated overview of embryological mechanisms, diagnostic strategies, and prenatal therapeutic advances in SB treatment, with emphasis on prenatal repair, fetal surgery and emerging regenerative approaches. Full article

BST2 has emerged as a multifunctional molecule that bridges antiviral defense, membrane architecture, and tumor immunity. Originally characterized as an interferon-inducible restriction factor that tethers virions to the plasma membrane, BST2 is now recognized as an oncogenic driver and immunoregulatory hub in diverse malignancies. In cancer, BST2 expression is frequently upregulated through promoter hypomethylation and transcriptional activation. Functionally, BST2 promotes proliferation, epithelial–mesenchymal transition, anoikis resistance, and chemoresistance, whereas its loss sensitizes tumor cells to proteotoxic and metabolic stresses. Beyond tumor cells, BST2 modulates the tumor microenvironment by promoting M2 macrophage infiltration, dendritic cell exhaustion, and natural killer (NK)-cell resistance, thereby contributing to immune evasion. Elevated BST2 expression correlates with poor prognosis in glioblastoma, breast, nasopharyngeal, and pancreatic cancers, and it serves as a circulating biomarker within small extracellular vesicles. In conclusion, BST2 is a dual-function molecule that integrates oncogenic signaling and immune regulation, making it an attractive diagnostic and therapeutic target for hematological and solid tumors. Full article

The global burden of acute and chronic liver diseases warrants safe and effective regenerative therapies that can complement or defer liver transplantation. Mesenchymal stromal/stem cells (MSCs) have been recognized as versatile biologics that modulate inflammation, reverse fibrosis, and promote hepatic repair predominantly through paracrine signaling. In hepatic milieu, MSCs act on hepatocytes, hepatic stellate cells, endothelial cells, and immune cell subsets through trophic factors and extracellular vesicles (EVs). Despite demonstrating hepatocyte-like differentiation of MSCs, their in vivo efficacy is primarily attributed to micro-environmental reprogramming rather than durable engraftment. This review covers MSC biology, liver regeneration, and cell-based versus EV therapies, including administration, dosing, quality, and safety. Future directions focus on biomarkers, multi-center trials, and engineered MSC/EV platforms for scalable personalized liver regeneration. Full article

With the intensification of global population aging, the co-morbidity rate of periodontitis and osteoporosis has significantly increased. The two are pathologically intertwined, forming a vicious cycle characterized by bone immunoregulatory dysfunction in the periodontal microenvironment, abnormal accumulation of reactive oxygen species (ROS), and disruption of bone homeostasis. Conventional mechanical debridement and anti-infective therapy can reduce the pathogen load, but in some patients, it remains challenging to achieve long-term stable control of inflammation and bone resorption. Furthermore, abnormal bone metabolism in the context of osteoporosis further weakens the osteogenic response during the repair phase, limiting the efficacy of these treatments. Bioinspired cell membrane-coated nanoparticles (CMNPs) have emerged as an innovative technological platform. By mimicking the biointerface properties of source cells—such as red blood cells, platelets, white blood cells, stem cells, and their exosomes—CMNPs enable targeted drug delivery, prolonged circulation within the body, and intelligent responses to pathological microenvironments. This review systematically explores how biomimetic design leverages the advantages of natural biological membranes to address challenges in therapeutic site enrichment and tissue penetration, in vivo circulation stability and effective exposure maintenance, and oxidative stress and immune microenvironment intervention, as well as functional regeneration supported by osteogenesis and angiogenesis. Additionally, we conducted an in-depth analysis of the key challenges encountered in translating preclinical research findings into clinical applications within this field, including issues such as the feasibility of large-scale production, batch-to-batch consistency, and long-term biosafety. This review lays a solid theoretical foundation for advancing the clinical translation of synergistic treatment strategies for periodontitis with osteoporosis and provides a clear research and development pathway. Full article

Diabetic wounds remain chronically non-healing due to impaired angiogenesis, persistent inflammation, and defective extracellular matrix remodelling. In recent years, stem cell-derived exosomes have emerged as a potent cell-free regenerative strategy capable of recapitulating the therapeutic benefits of mesenchymal stem cells while avoiding risks associated with direct cell transplantation. This review critically evaluates the preclinical evidence supporting the use of exosomes derived from adipose tissue, bone marrow, umbilical cord, and induced pluripotent stem cells for diabetic wound repair. These exosomes deliver bioactive cargos such as microRNAs, proteins, lipids, and cytokines that modulate key signalling pathways, including Phosphatidylinositol 3-kinase/Protein kinase (PI3K/Akt), Nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPK), Transforming growth factor-beta (TGF-β/Smad), and Hypoxia inducible factor-1α/Vascular endothelial growth factor (HIF-1α/VEGF), thereby promoting angiogenesis, accelerating fibroblast and keratinocyte proliferation, facilitating re-epithelialization, and restoring immune balance through M2 macrophage polarization. A central focus of this review is the recent advances in exosome-based delivery systems, including hydrogels, microneedles, 3D scaffolds, and decellularized extracellular matrix composites, which significantly enhance exosome stability, retention, and targeted release at wound sites. Comparative insights between stem cell therapy and exosome therapy highlight the superior safety, scalability, and regulatory advantages of exosome-based approaches. We also summarize progress in exosome engineering, manufacturing, quality control, and ongoing clinical investigations, along with challenges related to standardization, dosage, and translational readiness. Collectively, this review provides a comprehensive mechanistic and translational framework that positions stem cell-derived exosomes as a next-generation, cell-free regenerative strategy with the potential to overcome current therapeutic limitations and redefine clinical management of diabetic wound healing. Full article

Chimeric antigen receptor (CAR) cell therapies have revolutionized cancer immunotherapy by enabling targeted and potent antitumor immune responses. However, clinical challenges such as limited efficacy in solid tumors, severe toxicities including cytokine release syndrome (CRS), and manufacturing complexities restrict their broader use. Recently, CAR cell-derived exosomes (CAR-Exos) have emerged as promising cell-free therapeutic alternatives that retain the key antitumor functionalities of their parent cells while potentially overcoming the limitations of live cellular therapies. These nanoscale vesicles can deliver bioactive CAR molecules, cytotoxic proteins, and immunomodulatory cargo, enabling targeted tumor cell killing with reduced systemic toxicity and offering “off-the-shelf” applicability. This review comprehensively explores the biology, engineering, and therapeutic potential of CAR-Exos derived from T cells, natural killer (NK) cells, and other immune effectors. We discuss advances in isolation, characterization, and cargo profiling techniques, as well as preclinical and early clinical data supporting their application. Further, we address translational challenges including large-scale production, biodistribution, and immune evasion in tumor microenvironments. Combining cellular and exosomal CAR platforms holds promise to enhance efficacy and safety in cancer treatment, representing a frontier in targeted immunotherapy. Full article

Peripheral nerve injuries, particularly those involving the sciatic nerve, remain a major clinical challenge due to incomplete functional recovery and the limited translation of preclinical advances into effective therapies. This review synthesizes current evidence on the phase-specific evaluation of sciatic nerve regeneration in preclinical models, integrating behavioral, sensory, electrophysiological, and morphological approaches across the acute, subacute (Wallerian degeneration), early regenerative, and late regenerative phases. By mapping functional readouts onto the underlying biological events of each phase, we highlight how tools such as the Sciatic Functional Index, Beam Walk test, Rotarod test, nerve conduction studies, and nociceptive assays provide complementary and often non-interchangeable information about motor, sensory, and neuromuscular recovery. We further examine emerging therapeutic strategies, including intraoperative electrical stimulation, immunomodulation, platelet-rich plasma, bioengineered scaffolds, conductive and piezoelectric conduits, exosome-based hydrogels, tacrolimus delivery systems, and small molecules, emphasizing the importance of aligning their mechanisms of action with the dynamic microenvironment of peripheral nerve repair. Despite substantial advancements in experimental models, an analysis of publication trends and registries reveals a persistent translational gap, with remarkably few clinical trials relative to the high volume of preclinical studies. To illustrate how mechanistic insights can be complemented by molecular-level characterization, we also present a targeted computational analysis of alpha-lipoic acid (ALA,) including frontier orbital energies, physicochemical descriptors, and docking interactions with IL-6, TGF-β, and a growth-factor receptor—performed solely for this molecule due to its documented structural availability and relevance. By presenting an integrated, phase-specific framework for functional assessment and therapeutic evaluation, this review underscores the need for standardized, biologically aligned methodologies to improve the rigor, comparability, and clinical relevance of future studies in sciatic nerve regeneration. Full article

The development of safer, more effective, and tumor-specific therapeutic strategies remains a major challenge in oncology. Conventional treatments such as chemotherapy and radiotherapy often cause severe side effects and are limited in their ability to target deep-seated or resistant tumors. In this context, sonodynamic therapy (SDT) has emerged as a promising, non-invasive option, harnessing low-intensity ultrasound to activate sonosensitizers deep within tissues and generate cytotoxic reactive oxygen species (ROS) that selectively induce cancer cell death. Interestingly, SDT can also be combined with other therapies to achieve synergistic effects. However, despite encouraging preclinical results, SDT clinical translation is hindered by the poor aqueous solubility, instability, and low tumor specificity of traditional sonosensitizers. To overcome these limitations, recent studies have focused on employing extracellular vesicles (EVs), especially exosomes, as natural, biomimetic nanocarriers for sonosensitizer delivery. EVs offer unique advantages, including high biocompatibility, low immunogenicity, and intrinsic tumor-targeting ability, which make them ideal platforms for improving the therapeutic precision of SDT. Although several delivery strategies have been proposed, a comprehensive and focused overview of approaches specifically designed to enhance SDT performance using EVs is currently lacking. This review summarizes recent advances in integrating EVs with SDT for cancer treatment. It discusses the mechanisms underlying SDT, the engineering strategies developed to enhance exosome functionality, and the synergistic effects achieved through this combination. Furthermore, this review emphasizes that EV-based SDT not only enhances tumor accumulation of the therapeutic nanoplatforms, but also actively remodels the tumor microenvironment by improving oxygen availability, reversing immunosuppressive conditions, and triggering durable antitumor responses. Finally, the review addresses the translational challenges and outlines the critical future directions required to advance this promising therapeutic approach toward clinical application. Full article