The potential of the cell lysate, secretome, and extracellular vesicles (EVs) of mesenchymal stem cells (MSCs) to modulate the immune response and promote tissue regeneration has positioned them as a promising option for cell-free therapy. Currently, many clinical trials in stem cells-derived EVs and secretome are in progress various diseases and sometimes the results are failing. The major challenge on this roadmap is the lack of a standard extraction method for exosome, secretome, and lysate. The most optimal method for obtaining the secretome of MSCs for clinical utilization involves a comprehensive approach that includes non-destructive collection methods, time optimization, multiple collection rounds, optimization of culture conditions, and quality control measures. Further research and clinical studies are warranted to validate and refine these methods for safe and effective utilization of the MSC exosome, secretome, and lysate in various clinical applications. To address these challenges, it is imperative to establish a standardized and unified methodology to ensure reliable evaluation of these extractions in clinical trials. This review seeks to outline the pros and cons of methods for the preparation of MSCs-derived exosome, and secretome/lysate, and comparative analysis of their therapeutic potential.

From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.

Despite considerable advancements in understanding the mechanisms of ALI, the therapeutic options available in clinical practice remain predominantly supportive, highlighting the urgent need for innovative treatments. In this study, we investigated the potential protective benefits of extracellular vehicles from the probiotic strain Lactiplantibacillus plantarum (LpEVs) in ALI mouse model. We revealed that LpEVs administration attenuated LPS-induced ALI, as evidenced by reduced lung pathology, decreased inflammatory markers, and mitigated ferroptosis. In vitro experiments demonstrated that LpEVs restrained ferroptosis and promoted a shift towards an anti-inflammatory macrophage phenotype. Moreover, LpEVs increased the expression of NRF2, resulting in the promotion of HO1 and strengthening anti-ferroptotic System Xc-/GPX4 axis. Our analysis revealed that LpEVs alleviated ALI through the suppression of macrophages ferroptosis by delivering cbn-let-7 targeting ferroptosis-related gene Acsl4. These findings propose LpEVs as a promising therapeutic approach for preventing and treating ALI, highlighting the potential of leveraging probiotic-derived biomolecules to develop novel therapeutic strategies.

The critical role of the immune system in brain function and dysfunction is well recognized, yet development of immune therapies for psychiatric diseases has been slow due to concerns about iatrogenic immune deficiencies. These concerns are emphasized by the lack of objective diagnostic tools in psychiatry. A promise to resolve this conundrum lies in the exploitation of extracellular vesicles (EVs) that are physiologically produced or can be synthetized. EVs regulate recipient cell functions and offer potential for EVs-based therapies. Intranasal EVs administration enables the targeting of specific brain regions and functions, thereby facilitating the design of precise treatments for psychiatric diseases. The development of such therapies requires navigating four dynamically interacting networks: neuronal, glial, immune, and EVs. These networks are profoundly influenced by brain fluid distribution. They are crucial for homeostasis, cellular functions, and intercellular communication. Fluid abnormalities, like edema or altered cerebrospinal fluid (CSF) dynamics, disrupt these networks, thereby negatively impacting brain health. A deeper understanding of the above-mentioned four dynamically interacting networks is vital for creating diagnostic biomarker panels to identify distinct patient subsets with similar neuro-behavioral symptoms. Testing the functional pathways of these biomarkers could lead to new therapeutic tools. Regulatory approval will depend on robust preclinical data reflecting progress in these interdisciplinary areas, which could pave the way for the design of innovative and precise treatments. Highly collaborative interdisciplinary teams will be needed to achieve these ambitious goals.

The regenerative properties of exosomes make them especially appealing to treat skin and hair diseases. Preclinical studies suggest that exosomes may fuel hair growth by stimulating dermal papilla cells, activating hair follicle stem cells, and promoting angiogenesis. However, very limited data are available on the safety and efficacy of exosome use in human subjects.

To review the published literature on exosome use in human subjects with a focus on safety and the challenges facing clinical implementation in the treatment of androgenetic and nonscarring alopecias.

A review was conducted of PubMed, EMBASE, and Cochrane databases and included 48 studies. Twenty-five studies were clinical trials, 14 case reports, 4 case series, 1 retrospective review, and 4 conference abstracts.

Nine clinical studies were found relevant to alopecia. One hundred twenty-five patients received an exosome treatment for hair loss. Side effects were rare. However, in the broader field of dermatology, at least 10 serious adverse events have been reported.

Although exosomes have many promising therapeutic applications, there is demand for larger well-designed clinical trials with extended follow-up periods to prove efficacy and a need for consistent manufacturing standards and regulatory oversight to ensure product safety.

Nonalcoholic fatty liver disease (NAFLD) manifests as chronic hepatic steatosis, occurring variably across people due to racial and genetic diversity. It represents a stage in the development of chronic liver disease, marked by fat accumulation, inflammatory responses, oxidative stress in the endoplasmic reticulum, and fibrosis as primary concerns. Understanding its underlying mechanisms remains a challenging and pivotal area of study. In the past, acute liver injury-related diseases were commonly treated with methods such as liver transplantation. However, the emergence of artificial liver has shifted focus to stem cell therapies. Unlike conventional drugs, stem cell therapies are continuously evolving. Despite being classified as drugs, stem cells demonstrated significant efficacy after multiple injections. Mesenchymal stem cells, unlike other types of stem cells, do not have the risk of tumor formation and low immunogenicity, reducing the hypersensitivity reactions associated with liver transplantation. Increasingly, studies suggest that mesenchymal stem cells hold promise in the treatment of chronic liver injury diseases. This review focuses on investigating the role of mesenchymal stem cells in chronic metabolic liver diseases, such as non-alcoholic fatty liver disease, and delves into their specific functions.

Small extracellular vesicles (sEVs) derived from mesenchymal stromal cells (MSCs) hold substantial promise for therapeutic applications, including immune modulation and tissue regeneration. However, challenges such as batch-to-batch variability, donor material diversity, and the lack of standardized potency testing remain significant barriers to clinical translation. The recent U.S. Food and Drug Administration (FDA) approval of Ryoncil (remestemcel-L) for steroid-refractory acute graft-versus-host disease (aGvHD) in pediatric patients represents a crucial milestone for MSC-based therapies, offering also valuable insights for the development of MSC-EV therapies. This approval highlights the critical need to address variability and standardization issues in MSC products. Strategies like immortalizing MSCs and expanding them clonally can improve scalability, consistency, and overcome limitations inherent to cellular MSC therapies. With the FDA's decision signaling significant progress, optimizing MSC expansion protocols and refining potency testing methods will be crucial for advancing MSC-EVs as a viable therapeutic option, overcoming current challenges, and expanding clinical applications.

Current decade witnessed the emergence and re-emergence of many viruses, which affected public health significantly. Viruses mainly utilize host cell machinery to promote its growth, and spread of these diseases. Numerous factors influence virus-host cell interactions, of which extracellular vesicles play an important role, where they transfer information both locally and distally by enclosing viral and host-derived proteins and RNAs as their cargo. Thus, they play a dual role in mediating virus infections by promoting virus dissemination and evoking immune responses in host organisms. Moreover, it acts as a double-edged sword during these infections. Advances in extracellular vesicles regulating emerging and reemerging virus infections, particularly in the context of SARS-CoV-2, Dengue, Ebola, Zika, Chikungunya, West Nile, and Japanese Encephalitis viruses are discussed in this review.

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene, leading to a low quantity of SMN protein in cells. This depletion of SMN protein preferentially leads to death of motor neurons and, consequently, muscle atrophy, in addition to defects in many other peripheral tissues. SMN protein is naturally loaded into extracellular vesicles (EVs), which are sub-micron-sized, membrane-bound particles released from all cell types. The innate ability of EVs to deliver cargo to recipient cells has caused these vesicles to gain interest as therapeutic delivery vehicles. In this study, we show that adenovirus-mediated overexpression of SMN protein in HepG2 cells leads to the release of EVs loaded with high levels of SMN protein into conditioned medium. Application of this medium to recipient cells in tissue culture led to uptake of the SMN protein, which subsequently transited to the nucleus and co-localized with Gemin2 protein, forming nuclear gem-like structures similar to the native SMN protein. Overall, this work demonstrates that SMN protein can be delivered to cells through EVs, which holds promise as a potential therapy for patients with SMA.

The Coronavirus Disease 2019 (COVID-19), caused by virus SARS-CoV-2, is characterized by massive inflammation and immune system imbalance. Despite the implementation of vaccination protocols, the accessibility of treatment remains uneven. Furthermore, the persistent threat of new variants underscores the urgent need for expanded research into therapeutic options for SARS-CoV-2. Mesenchymal stem cells (MSCs) are known for their immunomodulatory potential through the release of molecules into the extracellular space, either as soluble elements or carried by extracellular vesicles (EVs). The aim of this study was to evaluate the anti-inflammatory potential of EVs obtained from human adipose tissue (ASC-EVs) against SARS-CoV-2 infection. ASC-EVs were purified by size-exclusion chromatography, and co-culture assays confirmed that ASC-EVs were internalized by human lung cells and could colocalize with SARS-CoV-2 into early and late endosomes. To determine the functionality of ASC-EVs, lung cells were infected with SARS-CoV-2 in the presence of increasing concentrations of ASC-EVs, and the release of cytokines, chemokines and viruses were measured. While SARS-CoV-2 replication was significantly reduced only at the highest concentrations tested, multiplex analysis highlighted that lower concentrations of ASC-EV sufficed to prevent the production of immune modulators. Importantly, ASC-EVs did not contain detectable inflammatory cytokines, nor did they trigger inflammatory mediators, nor affect cellular viability. In conclusion, this work suggests that ASC-EVs have the potential to attenuate inflammation by decreasing the production of pro-inflammatory cytokines in lung cells following SARS-CoV-2 infection.

Developing strategies to improve the therapeutic efficacy of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in autoimmune diseases have garnered increased attention.

To evaluate whether rapamycin-induced autophagy within the systemic lupus erythematosus (SLE) inflammatory microenvironment (Rapa-SLE) augments the therapeutic effects of MSC-derived EVs in SLE.

The therapeutic potential of the resulting EVs (Rapa-SLE-EV) was assessed in MRL/lpr mice. Rapa-SLE-EVs were compared with EVs derived from MSCs from MSCs cultured with EV-depleted fetal bovine serum (FBS-EV), EVs from MSCs cultured with rapamycin-treated FBS (Rapa-FBS-EV), and EVs exposed to SLE serum without rapamycin (SLE-EV). The autoimmune response, renal function, and pathological damage were assessed among the mouse groups. Additionally, mechanistic investigations into the role of the anti-inflammatory protein IDO1 within the EVs.

Interaction with the SLE inflammatory microenvironment triggered autophagy in MSCs, which was further enhanced by rapamycin treatment. Rapa-SLE-EV administration significantly ameliorated the autoimmune response and renal damage in MRL/lpr mice, outperforming other MSC-EV groups. This treatment mitigated key manifestations of SLE, including reduced autoantibody levels, as well as splenomegaly, and lymphadenopathy. Furthermore, Rapa-SLE-EV demonstrated superior suppression of plasma inflammatory cytokines, preserved renal function, mitigated pathological damage, and reduced glomerular immune complex deposition. Mechanistically, Rapa-SLE-EV exhibits exceptional inhibitory effects on SLE-B cell function, benefited by the high expression of the anti-inflammatory protein IDO1, which was confirmed to enter SLE-B cells through EVs.

We developed a novel strategy to improve the therapeutic efficacy of MSC-EVs in SLE and confirmed that the immunomodulatory function of the MSC-EVs is enhanced through autophagic activation and interaction with the SLE serum microenvironment, a process likely benefited by the high expression of IDO1.

At present, cyclosporine (CsA) is the first-line treatment for Pure Red Cell Aplasia (PRCA), but CsA administration can be associated with a number of side effects due to its high toxicity. Therefore, it is urgent to explore a safe and effective treatment for elderly patients who cannot be treated with conventional doses of CsA, especially those with multiple complications. Allogeneic Stem Cell Transplantation (ASCT) for PRCA is a promising treatment, but reports of using umbilical cord blood (UCB) are very rare.

In this report, UCB and umbilical cord mesenchymal stem cells (UC-MSCs) combined with low-dose CsA (1-3mg/kg/d) were used to treat 3 elderly patients who were diagnosed with PRCA combined with multiple complications in heart, lung, and renal. The treatments were successful without complications, and 12 months after stem cell infusion, the blood tests of the patients came normal. Moreover, the function of the liver, heart, and kidney continued to be stable.

This report provides an effective regimen of using UCB and UC-MSCs combined with low-dose CsA (1-3 mg/kg/d) to treat PRCA, especially for elderly patients with multiple complications who cannot use the conventional dosage.

Exposure to ionizing radiation can induce harmful biological effects on the human body, particularly in cases of high-dose γ-irradiation affecting the gastrointestinal tract, bone marrow, skin and lung. Such exposures lead to lethal outcomes as individuals experience a breakdown in their immune system's ability to defend against pathogens, predisposing them to sepsis-induced multiple organ failures. Mesenchymal stromal/stem cells (MSCs) possess diverse biological characteristics, including immunomodulation, anti-inflammation and tissue regeneration. Off-the-shelf culture-expanded human bone marrow- or adipose tissue-derived MSCs are clinically available to treat graft-versus-host disease following hematopoietic cell transplantation and perianal fistulas in Crohn's disease in Japan. While preclinical studies showcase encouraging outcomes in radiation-induced injuries, the effectiveness of MSC transplantation in addressing acute radiation syndrome affecting organs in irradiated individuals is limited. Recent studies have highlighted MSC-releasing extracellular vesicles as nanoparticle substances responsible for outlining the mechanism of action and have identified various components, including proteins and microRNA, that serve as functional molecules. MSC-releasing extracellular vesicle-based therapy emerges as a promising avenue, offering a potential solution to the challenges posed by radiation-induced injuries. However, further investigation is required, especially regarding whether MSC-releasing extracellular vesicles have regenerative effects on tissue-resident stem cells. These unresolved issues represent key aspects that need to be addressed to optimize the therapeutic potential of cell-based and extracellular vesicle-based MSC therapies for interventions in the context of radiation-induced injuries.

Human mesenchymal stromal cells (hMSCs) are a naturally adherent cell type and one of the most studied cellular agents used in cell therapy over the last 20 years. Their mechanism of action has been primarily associated with paracrine signaling, which has contributed to an increase in the number of studies focused on hMSC-related extracellular vesicles (EVs).

In this study, we demonstrate for the first time that human telomerase reverse transcriptase (hTERT) immortalized hMSCs can be adapted to suspension culture, eliminating the need for microcarriers or other matrixes to support cell growth.

This novel cell line, named suspension hMSCs (S-hMSCs), has a doubling time of approximately 55 hours, with a growth rate of 0.423/d. Regarding its immunophenotype characteristics, S-hMSCs retained close to 90% of CD73 and CD105 expression levels, with the CD90 receptor being downregulated during the adherent to suspension adaptation process. An RNA sequencing analysis showed an upregulation of the transcripts coding for CD44, CD46 and CD47 compared to the expression levels in AT-hMSCs and hTERT-hMSCs. The cell line herein established was able to generate EVs using a chemically defined medium formulation with these nanoparticles averaging 150 nm in size and displaying the markers CD63, CD81, and TSG101, while not expressing the negative marker calnexin.

This body of evidence, combined with the visual confirmation of EV presence using transmission electron microscopy, demonstrates the EV-producing capabilities of the novel S-hMSCs. This cell line provides a platform for process development, drug discovery and translational studies in the EV field.

Deep partial-thickness burns have a significant impact on both the physical and mental health of patients. Our previous study demonstrated human Umbilical Cord Mesenchymal stem cells (hUCMSCs) could enhance the healing of severe burns in small animal burn models, such as rats. Furthermore, our team has developed a deep partial-thickness burn model in Bama miniature pigs, which can be utilized for assessing drug efficacy in preclinical trials for wound healing. Therefore, this study further determine the optimal dosage of hUCMSCs in future clinical practice by comparing the efficacy of low-to-high doses of hUCMSCs on deep partial-thickness burn wounds in Bama miniature pigs.

The male Bama miniature pigs (N = 8, weight: 23-28 kg and length: 71-75 cm) were used to establish deep partial-thickness burn models, which used a continuous pressure of 1 kg and contact times of 35 s by the invented electronic burn instrument at 100℃ to prepare 10 round burn wounds with diameter of 5 cm according to our previous report. And then, 0 × 10^7, 1 × 10^7, 2 × 10^7, 5 × 10^7 and 1 × 10^8 doses of hUCMSCs were respectively injected into burn wounds of their corresponding groups. After treatment for 7, 14 and 21 days, the burned wound tissues were obtained for histological evaluation, including HE staining for histopathological changes, immunohistochemistry for neutrophil (MPO+) infiltration and microvessel (CD31+) quantity, as well as Masson staining for collagen deposition. The levels of inflammatory factors TNF-α, IL-1β, IL-10 and angiogenesis factors angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), as well as collagen type-I/type-III of the wound tissues were quantified by ELISA.

All of doses hUCMSCs can significantly increase wound healing rate and shorten healing time of the deep partial-thickness burn pigs in a dose-dependent manner. Furthermore, all of doses hUCMSCs can significantly promote epithelialization and decreased inflammatory reaction of wound, including infiltration of inflammatory cells and levels inflammatory factors. Meanwhile, the amounts of microvessel were increased in all of doses hUCMSCs group than those in the burn group. Furthermore, the collagen structure was disordered and partially necrotized, and ratios of collagen type-I and type-III were significantly decreased in burn group (4:1 in normal skin tissue), and those of all hUCMSCs groups were significantly improved in a dose-dependent manner. In a word, 1 × 10^8 dose of hUCMSCs could regenerate the deep partial-thickness burn wounds most efficaciously compared to other dosages groups and the burn group.

This regenerative cell therapy study using hUCMSCs demonstrates the best efficacy toward a high dose, that is dose of 1 × 10^8 of hUCMSCs was used as a reference therapeutic dose for treating 20 cm2 deep partial-thickness burns wound in future clinical practice.

Lung diseases are associated with high morbidity and mortality rates, thereby jeopardizing human health and imposing a great burden on society. Currently, lung diseases are mainly treated with medications, oxygen therapy and mechanical ventilation, but these approaches are unable to effectively reduce the mortality rate. Therefore, lung transplantation remains the ultimate treatment for various chronic lung diseases, but this treatment is also hindered by the limited availability of lung sources, immature technology and a low survival rate after transplantation. With constant changes in the environment, pathogens, type and amount of harmful substances and the prevalence of respiratory diseases, there is an urgent need to identify alternative treatment methods. Research on stem cell therapy has been very successful in recent years, and mesenchymal stem cells (MSCs), together with their secretory bodies, play a significant therapeutic role. Extracellular vesicles of MSCs (MSC-EVs) are also major components of the paracrine secretion of MSCs, including exosomes, microvesicles, and apoptotic bodies, among which exosomes are the most typical. MSC-EVs are believed to be present in various tissues of the human body where they can carry proteins, DNA, RNA and biologically active factors, just to name a few. They can also transmit various biological signals to participate in different biological activities, including the maintenance of homeostasis within the tissue. Several studies have further demonstrated that MSCs and their generated extracellular vesicles play an important role in the treatment of diseases. In this paper, the origin, properties and roles of MSCs and MSC-EVs are reviewed, the mechanisms of different lung diseases, the limitations of current therapeutic options and the roles of MSC-EVs in Chronic Obstructive Pulmonary Disease, asthma, infectious lung disease, lung cancer, pulmonary fibrosis, pulmonary arterial hypertension, and acute lung injury/ acute respiratory distress syndrome are also discussed (Figure 1). In addition, the current limitations and possible future research directions are also discussed in view of providing new ideas for the role of MSC-EVs in the treatment of lung diseases.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, with its incidence rising due to improved survival rates of these infants. BPD results from a combination of prenatal and postnatal factors, such as mechanical ventilation, oxygen toxicity, and infections, all of which significantly impact the prognosis and growth of affected infants. Current treatment options for BPD are largely supportive and do not address the underlying pathology. Exosomes are cell-derived bilayer-enclosed membrane structures enclosing proteins, lipids, RNAs, growth factors, cytokines and metabolites. They have become recognized as crucial regulators of intercellular communication in various physiological and pathological processes. Previous studies have revealed the therapeutic potential of human umbilical cord mesenchymal stem cells-derived exosomes (HUCMSCs-Exos) in promoting tissue repair and regeneration. Therefore, HUCMSCs-Exos maybe a promising and effective therapeutic modality for BPD. In this review, we firstly provide a comprehensive overview of BPD, including its etiology and the mechanisms of lung injury. Then we detail the isolation, characterization, and contents of HUCMSCs-Exos, and discuss their potential mechanisms of HUCMSCs-Exos in BPD treatment. Additionally, we summarize current clinical trials and discuss the challenges in translating these findings from bench to bedside. This review aims to lay the groundwork for future clinical applications of HUCMSCs-Exos in treating BPD.

Exosomes, nano-sized extracellular vesicles, have emerged as a promising tool for the diagnosis and treatment of various intractable diseases, including chronic wounds and cancers. As our understanding of exosomes continues to grow, their potential as a powerful therapeutic modality in medicine is also expanding. This systematic review aims to examine the progress of exosome-based clinical trials and provide a comprehensive overview of the therapeutic perspectives of exosomes.

This systematic review strictly follows PRISMA guidelines and has been registered in PROSPERO, the International Prospective Register of Systematic Reviews. It encompasses articles from January 2000 to January 2023, sourced from bibliographic databases, with targeted search terms targeting exosome applications in clinical trials. During the screening process, strict inclusion and exclusion criteria were applied, including a focus on clinical trials utilizing different cell-derived exosomes for therapeutic purposes.

Among the 522 publications initially identified, only 10 studies met the stringent eligibility criteria after meticulous screening. The selection process involved systematically excluding duplicates and irrelevant articles to provide a transparent overview.

According to our systematic review, exosomes have promising applications in a variety of medical fields, including cell-free therapies and drug delivery systems for treating a variety of diseases, especially cancers and chronic wounds. To ensure safety, potency, and broader clinical applications, further optimization of exosome extraction, loading, targeting, and administration is necessary. While cell-based therapeutics are increasingly utilizing exosomes, this field is still in its infancy, and ongoing clinical trials will provide valuable insights into the clinical utility of exosomes.

Extracellular vesicles (EVs) are heterogeneous membrane-like vesicles secreted by living cells that are involved in many physiological and pathological processes and act as intermediaries of intercellular communication and molecular transfer. Recent studies have shown that EVs from specific sources regulate tissue repair and regeneration by delivering proteins, lipids, and nucleic acids to target cells as signaling molecules. Nanotechnology breakthroughs have facilitated the development and exploration of engineered EVs for tissue repair. Enhancements through gene editing, surface modification, and content modification have further improved their therapeutic efficacy. This review summarizes the potential of EVs in tissue repair and regeneration, their mechanisms of action, and their research progress in regenerative medicine. This review highlights their design logic through typical examples and explores the development prospects of EVs in tissue repair. The aim of this review is to provide new insights into the design of EVs for tissue repair and regeneration applications, thereby expanding their use in regenerative medicine.

Nuclear receptors (NRs) function as crucial transcription factors in orchestrating essential functions within the realms of development, host defense, and homeostasis of body. NRs have garnered increased attention due to their potential as therapeutic targets, with drugs directed at NRs demonstrating significant efficacy in impeding chronic disease progression. Consequently, these pharmacological agents hold promise for the treatment and management of various diseases. Accumulating evidence emphasizes the regulatory role of exosome-derived microRNAs (miRNAs) in chronic inflammation, disease progression, and therapy resistance, primarily by modulating transcription factors, particularly NRs. By exploiting inflammatory pathways such as protein kinase B (Akt)/mammalian target of rapamycin (mTOR), nuclear factor kappa-B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and Wnt/β-catenin signaling, exosomes and NRs play a pivotal role in the panorama of development, physiology, and pathology. The internalization of exosomes modulates NRs and initiates diverse autocrine or paracrine signaling cascades, influencing various processes in recipient cells such as survival, proliferation, differentiation, metabolism, and cellular defense mechanisms. This comprehensive review meticulously examines the involvement of exosome-mediated NR regulation in the pathogenesis of chronic ailments, including atherosclerosis, cancer, diabetes, liver diseases, and respiratory conditions. Additionally, it elucidates the molecular intricacies of exosome-mediated communication between host and recipient cells via NRs, leading to immunomodulation. Furthermore, it outlines the implications of exosome-modulated NR pathways in the prophylaxis of chronic inflammation, delineates current limitations, and provides insights into future perspectives. This review also presents existing evidence on the role of exosomes and their components in the emergence of therapeutic resistance.

Recently, there has been increasing attention to bidirectional information exchange between the brain and lungs. Typical physiological data is communicated by channels like the circulation and sympathetic nervous system. However, communication between the brain and lungs can also occur in pathological conditions. Studies have shown that severe traumatic brain injury (TBI), cerebral hemorrhage, subarachnoid hemorrhage (SAH), and other brain diseases can lead to lung damage. Conversely, severe lung diseases such as acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure can exacerbate neuroinflammatory responses, aggravate brain damage, deteriorate neurological function, and result in poor prognosis. A brain or lung injury can have adverse effects on another organ through various pathways, including inflammation, immunity, oxidative stress, neurosecretory factors, microbiome and oxygen. Researchers have increasingly concentrated on possible links between the brain and lungs. However, there has been little attention given to how the interaction between the brain and lungs affects the development of brain or lung disorders, which can lead to clinical states that are susceptible to alterations and can directly affect treatment results. This review described the relationships between the brain and lung in both physiological and pathological conditions, detailing the various pathways of communication such as neurological, inflammatory, immunological, endocrine, and microbiological pathways. Meanwhile, this review provides a comprehensive summary of both pharmacological and non-pharmacological interventions for diseases related to the brain and lungs. It aims to support clinical endeavors in preventing and treating such ailments and serve as a reference for the development of relevant medications.

Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model.

In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically.

In vitro, IL-1β, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group.

Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI.

Diabetic foot ulcer (DFU), characterized by high recurrence rate, amputations and mortality, poses a significant challenge in diabetes management. The complex pathology involves dysregulated glucose homeostasis leading to systemic and local microenvironmental complications, including peripheral neuropathy, micro- and macro-angiopathy, recurrent infection, persistent inflammation and dysregulated re-epithelialization. Novel approaches to accelerate DFU healing are actively pursued, with a focus on utilizing exosomes. Exosomes are natural nanovesicles mediating cellular communication and containing diverse functional molecular cargos, including DNA, mRNA, microRNA (miRNA), lncRNA, proteins, lipids and metabolites. While some exosomes show promise in modulating cellular function and promoting ulcer healing, their efficacy is limited by low yield, impurities, low loading content and inadequate targeting. Engineering exosomes to enhance their curative activity represents a potentially more efficient approach for DFUs. This could facilitate focused repair and regeneration of nerves, blood vessels and soft tissue after ulcer development. This review provides an overview of DFU pathogenesis, strategies for exosome engineering and the targeted therapeutic application of engineered exosomes in addressing critical pathological changes associated with DFUs.

Exosomes exhibit high bioavailability, biological stability, targeted specificity, low toxicity, and low immunogenicity in shuttling various bioactive molecules such as proteins, lipids, RNA, and DNA. Natural exosomes, however, have limited production, targeting abilities, and therapeutic efficacy in clinical trials. On the other hand, engineered exosomes have demonstrated long-term circulation, high stability, targeted delivery, and efficient intracellular drug release, garnering significant attention. The engineered exosomes bring new insights into developing next-generation drug delivery systems and show enormous potential in therapeutic applications, such as tumor therapies, diabetes management, cardiovascular disease, and tissue regeneration and repair. In this review, we provide an overview of recent advancements associated with engineered exosomes by focusing on the state-of-the-art strategies for cell engineering and exosome engineering. Exosome isolation methods, including traditional and emerging approaches, are systematically compared along with advancements in characterization methods. Current challenges and future opportunities are further discussed in terms of the preparation and application of engineered exosomes.

The current study aimed to investigate the effects of human placental mesenchymal stromal cell-derived small extracellular vesicles (hPMSC-sEVs) as a treatment for COVID-19. This double-blind, randomized, controlled clinical trial was conducted on two groups of patients with COVID-19-associated acute respiratory distress syndrome. After randomization, the control group received standard treatment and placebo, and the intervention arm received standard treatment plus hPMSC-sEVs. The number of hospital deaths was considered the primary outcome. After meeting the exclusion and inclusion criteria, 21 and 24 patients were allocated to intervention and control arms, respectively. Besides admission SpO2 levels, which were significantly lower in the intervention arm (p = 0.008), all the baseline demo-biographic and laboratory variables were similar between the groups. It was shown that hPMSC-sEVs could significantly (p = 0.015) decrease the mortality ratio in the intervention group (4/21 [19.04%]) compared to the controls (13/24 [54.16%]). The mean time to death in the intervention and control groups was 28.06 and 11.10 days, respectively (p < 0.001). This study showed that hPMSC-sEVs are a possible treatment for critically ill patients with COVID-19.

Nowadays, it has become clear that extracellular vesicles (EVs) are not a cellular waste disposal vesicle but are an essential part of an intercellular communication system. Besides the use of EVs in biomarker studies and diagnostics, the potential of EV-therapeutics has been seen by many. They provide unique properties for disease therapy, including strong immune-modulatory actions, the possibility of engineering, low immunogenicity, and the capability of crossing biological barriers. Proof-of-concept of EV-therapeutics for various pathologies has been achieved in preclinical studies. However, clinical trials with EVs have only been emerging slowly. Here, we aim to provide a comprehensive overview of the current state-of-the-art concerning clinical studies using EVs in human therapy. By approaching the current knowledge in a systematic manner, we were able to include 21 reports for meta-analysis of safety and evaluation of efficacy outcomes. Overall, we have shown that EV-based therapy is safe with a low incidence of serious adverse events (SAE; 0.7% (95%-CI: 0.1-5.2%), and adverse events (AE; 4.4% (95%-CI: 0.7-22.2%). Subgroup analysis showed no significant difference in SAE when comparing autologous versus allogeneic administration, as well as engineered versus non-engineered EV products. A significantly higher number of AE was seen in autologous versus allogeneic administration. However, the clinical relevance remains questionable. Evaluation of the clinical outcomes of immunostimulatory, immunosuppressive or regenerative EV-therapies indicated improvement in the majority of treated patients. Despite these promising results, data need to be approached with caution due to a high heterogeneity in the EVs manufacturing methods, study design, and reporting of (S)AE. Overall, we conclude that EV-based therapy is safe and presents a promising opportunity in therapy. More efforts are needed in the standardization and harmonization of reporting of EV isolation and characterization data as well as in the reporting of (S)AE to allow inter-study comparison.

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this issue, the current study introduces solid lipid nanoparticles encapsulating hydrophobic dexamethasone palmitate (DXMS-Pal-SLNs) as an anti-inflammatory nanoplatform to treat pneumonia. The specialized nanoparticle formulation is characterized by high drug loading efficiency, low drug leakage and excellent colloidal stability in particular during nebulization and is proficiently designed to target alveolar macrophages in deep lung regions via local delivery with the nebulization administration. In vitro analyses revealed substantial reductions in the secretions of tumor necrosis factor-α and interleukin-6 from alveolar macrophages, highlighting the potential efficacy of DXMS-Pal-SLNs in alleviating pneumonia-related inflammation. Similarly, in vivo experiments showed a significant reduction in the levels of these cytokines in the lungs of mice experiencing lipopolysaccharide-induced pulmonary inflammation after the administration of DXMS-Pal-SLNs via nebulization. Furthermore, the study demonstrated that DXMS-Pal-SLNs effectively control acute infections without causing pulmonary infiltration or excessive recruitment of immunocytes in lung tissues. These findings highlight the potential of nebulized DXMS-Pal-SLNs as a promising therapeutic strategy for mitigating pneumonia-related inflammations.

Extracellular vesicles (EVs) have the innate ability to carry proteins, lipids, and nucleic acids between cells, and thus these vesicles have gained much attention as potential therapeutic delivery vehicles. Many strategies have been explored to enhance the loading of specific cargoes of interest into EVs, which could result in the delivery of more therapeutic to recipient cells, thus enhancing therapeutic efficacy. In this review, we discuss the natural biogenesis of EVs, the mechanism by which proteins and nucleic acids are selected for inclusion in EVs, and novel methods that have been employed to enhance loading of specific cargoes into EVs. As well, we discuss biodistribution of administered EVs in vivo and summarize clinical trials that have attempted to harness the therapeutic potential of EVs.

Cardiovascular complications are the most deadly and cost-driving effects of diabetes mellitus (DM). One of them, which is steadily attracting attention among scientists, is diabetes-induced heart failure, also known as diabetic cardiomyopathy (DCM). Despite significant progress in the research concerning the disease, a universally accepted definition is still lacking. The pathophysiology of the processes accelerating heart insufficiency in diabetic patients on molecular and cellular levels also remains elusive. However, the recent interest concerning extracellular vesicles (EVs) has brought promise to further clarifying the pathological events that lead to DCM. In this review, we sum up recent investigations on the involvement of EVs in DCM and show their therapeutic and indicatory potential.

Mesenchymal stem cells (MSCs) have important research value and broad application prospects in cardiovascular diseases (CVDs). However, few bibliometric analyses on MSCs in cardiovascular diseases are available. This study aims to provide a thorough review of the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in cardiovascular diseases, with the provision of discoveries in the latest progress, evolution paths, frontier research hotspots, and future research trends in the regarding field.

The articles related to MSCs in cardiovascular diseases were retrieved from the Web of Science. The bibliometric study was performed by CiteSpace and VOSviewer, and the knowledge map was generated based on data obtained from retrieved articles.

In our study, a total of 4,852 publications launched before August 31, 2023 were accessed through the Web of Science Core Collection (WoSCC) database via our searching strategy. Significant fluctuations in global publications were observed in the field of MSCs in CVDs. China emerged as the nation with the largest number of publications, yet a shortage of high-quality articles was noted. The interplay among countries, institutions, journals and authors is visually represented in the enclosed figures. Importantly, current research trends and hotspots are elucidated. Cluster analysis on references has highlighted the considerable interest in exosomes, extracellular vesicles, and microvesicles. Besides, keywords analysis revealed a strong emphasis on myocardial infarction, therapy, and transplantation. Treatment methods-related keywords were prominent, while keywords associated with extracellular vesicles gathered significant attention from the long-term perspective.

MSCs in CVDs have become a topic of active research interest, showcasing its latent value and potential. By summarizing the latest progress, identifying the research hotspots, and discussing the future trends in the advancement of MSCs in CVDs, we aim to offer valuable insights for considering research prospects.

Cytokine release syndrome (CRS) is an acute systemic inflammatory reaction in which hyperactivated immune cells suddenly release a large amount of cytokines, leading to exaggerated inflammatory responses, multiple organ dysfunction, and even death. Although palliative treatment strategies have significantly reduced the overall mortality, novel targeted treatment regimens with superior therapy efficacy are urgently needed. Vascular endothelial cells (ECs) are important target cells of systemic inflammation, and their destruction is considered to be the initiating event underlying many serious complications of CRS. Mesenchymal stem/stromal cells (MSCs) are multipotent cells with self-renewing differentiation capacity and immunomodulatory properties. MSC transplantation can effectively suppress the activation of immune cells, reduce the bulk release of cytokines, and repair damaged tissues and organs. Here, we review the molecular mechanisms underlying CRS-induced vascular endothelial injury and discuss potential treatments using MSCs. Preclinical studies demonstrate that MSC therapy can effectively repair endothelium damage and thus reduce the incidence and severity of ensuing CRS-induced complications. This review highlights the therapeutic role of MSCs in fighting against CRS-induced EC damage, and summarizes the possible therapeutic formulations of MSCs for improved efficacy in future clinical trials.

Circular RNAs (circRNAs) have emerged as pivotal regulators of gene expression and cellular processes in various physiological and pathological conditions. In recent years, there has been a growing interest in investigating the role of circRNAs in inflammatory lung diseases, owing to their potential to modulate inflammation-associated pathways and contribute to disease pathogenesis. Inflammatory lung diseases, like asthma, chronic obstructive pulmonary disease (COPD), and COVID-19, pose significant global health challenges. The dysregulation of inflammatory responses demonstrates a pivotal function in advancing these diseases. CircRNAs have been identified as important players in regulating inflammation by functioning as miRNA sponges, engaging with RNA-binding proteins, and participating in intricate ceRNA networks. These interactions enable circRNAs to regulate the manifestation of key inflammatory genes and signaling pathways. Furthermore, emerging evidence suggests that specific circRNAs are differentially expressed in response to inflammatory stimuli and exhibit distinct patterns in various lung diseases. Their involvement in immune cell activation, cytokine production, and tissue remodeling processes underscores their possible capabilities as therapeutic targets and diagnostic biomarkers. Harnessing the knowledge of circRNA-mediated regulation in inflammatory lung diseases could lead to the development of innovative strategies for disease management and intervention. This review summarizes the current understanding of the role of circRNAs in inflammatory lung diseases, focusing on their regulatory mechanisms and functional implications.

COVID-19 rapidly escalated into a worldwide pandemic with elevated infectivity even from asymptomatic patients. Complications can lead to severe pneumonia and acute respiratory distress syndrome (ARDS), which are the main contributors to death. Because of their regenerative and immunomodulatory capacities, stem cells and their derived extracellular vesicles (EVs) are perceived as promising therapies against severe pulmonary conditions, including those associated with COVID-19. Herein, we evaluate the safety and efficacy of stem cell EVs in treating COVID-19 and complicating pneumonia, acute lung injury, and ARDS. We also cover relevant preclinical studies to recapitulate the current progress in stem cell EV-based therapy.

Using PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science, we searched for all English-language published studies (2000-2023) that used stem cell EVs as a therapy for COVID-19, ARDS, or pneumonia. The risk of bias (ROB) was assessed for all studies.

Forty-eight studies met our inclusion criteria. Various-sized EVs derived from different types of stem cells were reported as a potentially safe and effective therapy to attenuate the cytokine storm induced by COVID-19. EVs alleviated inflammation and regenerated the alveolar epithelium by decreasing apoptosis, proinflammatory cytokines, neutrophil infiltration, and M2 macrophage polarization. They also prevented fibrin production and promoted the production of anti-inflammatory cytokines and endothelial cell junction proteins.

Similar to their parental cells, stem cell EVs mediate lung tissue regeneration by targeting multiple pathways and thus hold promise in promoting the recovery of COVID-19 patients and improving the survival rate of severely affected patients.

Stem cells (SCs) have been used therapeutically for decades, yet their applications are limited by factors such as the risk of immune rejection and potential tumorigenicity. Extracellular vesicles (EVs), a key paracrine component of stem cell potency, overcome the drawbacks of stem cell applications as a cell-free therapeutic agent and play an important role in treating various diseases. However, EVs derived from two-dimensional (2D) planar culture of SCs have low yield and face challenges in large-scale production, which hinders the clinical translation of EVs. Three-dimensional (3D) culture, given its ability to more realistically simulate the in vivo environment, can not only expand SCs in large quantities, but also improve the yield and activity of EVs, changing the content of EVs and improving their therapeutic effects. In this review, we briefly describe the advantages of EVs and EV-related clinical applications, provide an overview of 3D cell culture, and finally focus on specific applications and future perspectives of EVs derived from 3D culture of different SCs.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection typically presents with fever and respiratory symptoms, which can progress to severe respiratory distress syndrome and multiple organ failure. In severe cases, these complications may even lead to death. One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response. Therefore, suppressing the overactive immune response may be an effective strategy for treating COVID-19. Mesenchymal stem cells (MSCs) and their derived exosomes (MSCs-Exo) have potent homing abilities, immunomodulatory functions, regenerative repair, and antifibrotic effects, promising an effective tool in treating COVID-19. In this paper, we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19. We also summarize relevant recent clinical trials, including the source of cells, the dosage and the efficacy, and the clinical value and problems in this field, providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

MiRNAs are a class of small non-coding RNAs, which regulate gene expression post-transcriptionally by partial complementary base pairing. Aberrant miRNA expressions have been reported in tumor tissues and peripheral blood of cancer patients. In recent years, artificial intelligence algorithms such as machine learning and deep learning have been widely used in bioinformatic research. Compared to traditional bioinformatic tools, miRNA target prediction tools based on artificial intelligence algorithms have higher accuracy, and can successfully predict subcellular localization and redistribution of miRNAs to deepen our understanding. Additionally, the construction of clinical models based on artificial intelligence algorithms could significantly improve the mining efficiency of miRNA used as biomarkers. In this article, we summarize recent development of bioinformatic miRNA tools based on artificial intelligence algorithms, focusing on the potential of machine learning and deep learning in cancer-related miRNA research.

Recent studies demonstrated that mesenchymal stem cells (MSCs) are important for the cell-based therapy of diseased or injured lung due to their immunomodulatory and regenerative properties as well as limited side effects in experimental animal models. Preclinical studies have shown that MSCs have also a remarkable effect on the immune cells, which play major roles in the pathogenesis of multiple lung diseases, by modulating their activity, proliferation, and functions. In addition, MSCs can inhibit both the infiltrated immune cells and detrimental immune responses in the lung and can be used in treating lung diseases caused by a virus infection such as Tuberculosis and SARS-COV-2. Moreover, MSCs are a source for alveolar epithelial cells such as type 2 (AT2) cells. These MSC-derived functional AT2-like cells can be used to treat and diminish serious lung disorders, including acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis in animal models. As an alternative MSC-based therapy, extracellular vesicles that are derived from MSC-derived can be employed in regenerative medicine. Herein, we discussed the key research findings from recent clinical and preclinical studies on the functions of MSCs in treating some common and well-studied lung diseases. We also discussed the mechanisms underlying MSC-based therapy of well-studied lung diseases, and the recent employment of MSCs in both the attenuation of lung injury/inflammation and promotion of the regeneration of lung alveolar cells after injury. Finally, we described the role of MSC-based therapy in treating major pulmonary diseases such as pneumonia, COPD, asthma, and idiopathic pulmonary fibrosis (IPF).

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.