This review systematically examines the biogenesis of MSC-EVs, focusing specifically on exosomes, microvesicles, and apoptotic vesicles, and introduces an emerging approach utilizing engineered MSC aggregate-derived EVs inspired by organ morphogenesis.
Abstract
Abstract Regenerative medicine is undergoing a paradigm shift from live-cell therapies to cell-free strategies. Within this evolving field, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a leading platform. These nanoscale vesicles deliver bioactive cargo that mediates critical therapeutic functions, including immunomodulation, angiogenesis, and anti-fibrosis. Furthermore, they offer improved safety, greater potential for standardization, and enhanced scalability compared to traditional live-cell therapies. However, clinical translation remains constrained by several challenges, such as inherent vesicle heterogeneity, limited targeting specificity, and bottlenecks in large-scale manufacturing. This review systematically examines the biogenesis of MSC-EVs, focusing specifically on exosomes, microvesicles, and apoptotic vesicles. We evaluate their functional performance across diverse regeneration contexts, encompassing orofacial, barrier, musculoskeletal, and visceral tissue regeneration. We further highlight innovative engineering strategies designed to enhance therapeutic efficacy, such as surface modification, cargo loading, and biomaterial-integrated delivery systems. In addition, we introduce an emerging approach utilizing engineered MSC aggregate-derived EVs inspired by organ morphogenesis. Finally, this article details the strategic framework required for clinical translation. The framework encompasses scalable production, rigorous quality control, comprehensive non-clinical studies, evolving regulatory pathways, and the current clinical trial landscape. Collectively, this work provides an integrated roadmap for advancing MSC-EVs as a next-generation precision platform for cell-free therapeutics.
Mesenchymal stromal/stem cell-derived extracellular vesicles (MSC-EVs), including preparations frequently described as exosomes, are being investigated as cell-free candidates for tissue repair. These lipid-bilayer-delimited particles carry proteins, lipids, and nucleic acids that may modulate immune responses, cell survival, angiogenesis, proliferation, migration, and extracellular-matrix remodeling in experimental systems. This review summarizes the biological characteristics of MSC-EVs, commonly used separation methods, proposed mechanisms of action, and preclinical applications in peripheral nerve repair, bone regeneration, and cutaneous wound healing. It also considers major barriers to translation, including inconsistent nomenclature and characterization, variable yield, purity, composition, and potency, limited tissue retention and targeting, and the absence of broadly standardized, scalable manufacturing processes. Future studies should use rigorous EV characterization, mechanism-linked potency assays, reproducible production protocols, and appropriately designed preclinical and clinical studies to establish the safety and efficacy of MSC-EV-based interventions.
Mesenchymal stem cells (MSCs) have attracted considerable attention for clinical translation in regenerative medicine, primarily due to their validated paracrine effects, prominent immunomodulatory properties, and superior multipotent differentiation capabilities. However, the limited homing efficiency and poor post-transplant survival of MSCs severely compromise therapeutic efficacy, thereby giving rise to suboptimal and inconsistent treatment outcomes. To circumvent these critical drawbacks and fully harness the therapeutic potential of MSCs, researchers have incorporated a diverse array of effective strategies, including genetic engineering, preconditioning with cytokines, small molecular compounds or hypoxic stimuli, and scaffold-based culture systems. Given these promising research advances, this review systematically summarizes recent advances in MSC-enhanced therapeutic strategies, and elaborates on their core molecular mechanisms as well as how these mechanisms modulate MSC survival, homing capacity and immunomodulatory efficacy. On this basis, we further analyze the practical applicability of these enhanced MSCs in clinical trials and seek to provide critical insights for the clinical selection of MSC-based enhanced therapies.
Shanshan Zheng, Yukang Huang, Xianli Yang et al.· Frontiers in Cell and Develo...· 0 citations
Highlights What are the main findings? In various clinical trials, largely unmodified mesenchymal stem cell (MSC) therapies have shown limited and inconsistent benefits, highlighting the need for a shift toward MSC products engineered to target specific mechanisms and diseases. Targeted engineering, such as genetic modification, hematopoietic cell E-/L-selectin ligand (HCELL)/CD44 and E-selectin glycoengineering, hypoxic/cytokine preconditioning, biomaterial scaffolding, and MSC-derived extracellular vesicles, may address core limitations of unmodified MSCs by improving homing, persistence, immunomodulation, and resistance to senescence in preclinical models, which may in turn contribute to healthspan-relevant outcomes. What are the implications of the main findings? Disease-matched and combinatorial engineering could establish MSCs as a flexible therapeutic platform for treating age-related diseases and potentially improving healthspan-related outcomes rather than lifespan alone. Clinical translation will depend on standardized manufacturing, validated potency and senescence resistance assays, long-term monitoring of tumorigenicity, and regulatory frameworks suited to aged recipients. Abstract Engineered mesenchymal stem cells (MSCs) have emerged as promising therapeutic platforms for healthspan-relevant applications. As agents of tissue repair and modulators of biological aging, MSCs have been widely studied for their capacity to enhance regeneration, restore immune homeostasis, and reduce chronic inflammation associated with age-related decline. This review examines emerging bioengineering strategies designed to overcome key age-related limitations in MSC homing, survival, and paracrine signaling, which have historically constrained their in vivo efficacy. We discuss major engineering approaches, including genetic modification, surface engineering, metabolic reprogramming, and preconditioning, with particular attention to their contributions to longevity-focused applications. Preclinical studies have demonstrated that engineered MSCs and their extracellular vesicles (EVs) yield measurable improvements in therapeutic performance. Reported benefits include prolonged persistence in inflamed tissues, partial reversal of senescence-associated phenotypes, and modulation of pro-aging inflammatory pathways. While MSC-derived EVs may offer potential safety advantages and could reduce certain risks associated with live-cell administration, this remains to be confirmed in well-controlled clinical studies, and significant challenges persist in terms of manufacturing scalability, cargo consistency, and process standardization. The current literature, which is predominantly preclinical, supports the potential of engineered MSC platforms to improve healthspan-relevant outcomes; direct evidence of healthspan extension in humans is not yet available. However, successful clinical translation will require a standardized manufacturing process to ensure therapeutic safety, reproducibility, and efficacy in age-related conditions.
Anne-Isabelle S. Reme, Mela Lew, Yulexi Y. Ortiz et al.· Cells· 0 citations
Abstract Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.
Lu-Ming Pan, Bao-Cai Liu, Jing-Jian Xu et al.· International Journal of Nan...· 0 citations
Extracellular vesicles (EVs) are promising cell-free therapeutic agents because of their low immunogenicity, excellent biocompatibility, and intrinsic capacity for intercellular communication. Of these, mesenchymal stem cell-derived EVs (MSC-EVs) have attracted considerable interest for their potential in treating optic neuropathies; however, their clinical translation remains limited by standardized manufacturing, quality evaluation, and mechanistic understanding. This review summarizes key advances in therapeutic EV development, including MSC culture, EV production, isolation, and characterization, with a focus on the current strategies and limitations of EV quality assessment. In addition, we propose a pathological-node-based framework to integrate the current evidence for EV therapies with optic neuropathies. Despite differences in EV sources, molecular composition, and proposed mechanisms, the therapeutic effects of diverse EV preparations converge on three shared pathological processes: retinal ganglion cell (RGC) preservation, neuroinflammatory regulation, and metabolic homeostasis maintenance. Finally, we discuss major challenges for clinical translation, including EV heterogeneity, functional EV subpopulations, targeted delivery, engineering strategies, and the establishment of biologically relevant potency assays. This review highlights the need to shift EV studies from empirical preparation toward mechanism-driven design and functional evaluation, thereby facilitating the development of clinically translatable EV-based therapies.
Jing Zhou, Xi Lin, Lijuan Yan et al.· Extracellular Vesicles and C...· 0 citations
Osteoarthritis (OA) is a common degenerative joint disease characterized by pain, stiffness, progressive cartilage loss, and reduced mobility. Current treatments primarily aim to relieve symptoms rather than restore damaged cartilage, and durable regeneration of native hyaline cartilage remains a major clinical challenge. Extracellular Vesicles (EVs), particularly those derived from Mesenchymal Stem Cells (MSCs), have emerged as promising cell-free therapeutic platforms because of their ability to modulate inflammation, regulate chondrocyte activity, and influence extracellular matrix metabolism. However, EV heterogeneity, source-dependent variability, limited targeting efficiency, inconsistent cargo loading, and lack of standardized manufacturing protocols continue to restrict their clinical translation. This review summarizes recent advances in engineered EV-based strategies for OA and cartilage repair, including parental-cell preconditioning, genetic modification, surface functionalization, cargo loading, artificial EV platforms, and biomaterial-assisted delivery. Importantly, we distinguish between in vitro findings, preclinical animal studies, and early clinical evidence to provide a balanced assessment of translational readiness. We also discuss key regulatory and safety challenges, including GMP-compliant production, batch-to-batch variability, quality-control criteria, potency assays, scalability, biodistribution, and long-term safety. By integrating EV engineering with translational and regulatory perspectives, this review highlights the potential of engineered EVs as future disease-modifying tools for OA while emphasizing that their clinical efficacy and capacity to restore durable hyaline cartilage remain to be demonstrated in robust human studies.
Shayan Boozarjomehri Amnie, Sina Mahmoudian, Mahdi Ghorbani et al.· Avicenna journal of medical...· 0 citations
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