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The therapeutic effects of extracellular vesicles (EVs) have been identified as a significant factor in intercellular communication in different disease treatments, including osteoarthritis (OA). Compared to the conventional approaches in treating OA, EV therapy is a non-invasive and cell-free method. However, improving the yield of EVs and their therapeutic effects are the main challenges for clinical applications. In this regard, researchers are using the EV engineering potential to overcome these challenges. New findings suggest that the co-culture strategy as an indirect EV engineering method efficiently increases EV production and quality. The co-culture of mesenchymal stem cells (MSCs) and chondrocytes has improved their chondrogenesis, anti-inflammatory effects, and regenerative properties which are mediated by EVs. Hence, co-culture engineering by considerable systems could be useful in producing engineered EVs for different therapeutic applications. Here, we review various co-culture approaches, including diverse direct and indirect, 2D and 3D cell cultures, as well as static and dynamic systems. Meanwhile, we suggest and discuss the advantages of combined strategies to achieve engineered EVs for OA treatment.

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The interleukin 6 (IL6) signaling pathway plays pleiotropic roles in regulating the inflammatory milieu that contributes to arthritis development. Here, we show that activation of IL6 trans-signaling induces phenotypic transitions in tissue-resident cells toward an inflammatory state. The establishment of arthritis increases the serum number of extracellular vesicles (EVs), while these EVs express more IL6 signal transducer (IL6ST, also known as gp130) on their surface. Transferring these EVs can block IL6 trans-signaling in vitro by acting as decoys that trap hyper IL6 and prevent inflammatory amplification in recipient arthritic mice. By genetically fusing EV-sorting domains with extracellular domains of receptors, we engineered EVs that harbor a higher quantity of signaling-incompetent decoy receptors. These exogenous decoy EVs exhibit significant potential in eliciting efficient anti-inflammatory effects in vivo. Our findings suggest an inherent resistance of decoy EVs against inflammation, highlighting the therapeutic potential of efficient decoy EVs in treating inflammatory diseases.

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The release of growth factors, cytokines and extracellular matrix modifiers by activated platelets is an important step in the process of healthy wound healing. Extracellular vesicles (EVs) released by activated platelets carry this bioactive cargo in an enriched form, and may therefore represent a potential therapeutic for the treatment of delayed wound healing, such as chronic wounds. While EVs show great promise in regenerative medicine, their production at clinical scale remains a critical challenge and their tolerability in humans is still to be fully established. In this work, we demonstrate that Ligand-based Exosome Affinity Purification (LEAP) chromatography can successfully isolate platelet EVs (pEVs) of clinical grade from activated platelets, which retain the regenerative properties of the parent cell. LEAP-isolated pEVs display the expected biophysical features of EV populations and transport essential proteins in wound healing processes, including insulin growth factor (IGF) and transforming growth factor beta (TGF-ß). In vitro studies show that pEVs induce proliferation and migration of dermal fibroblasts and increase dermal endothelial cells' angiogenic potential, demonstrating their wound healing potential. pEV treatment activates the ERK and Akt signalling pathways within recipient cells. In a first-in-human, double-blind, placebo-controlled, phase I clinical trial of healthy volunteer adults, designed primarily to assess safety in the context of wound healing, we demonstrate that injections of LEAP-purified pEVs in formulation buffer are safe and well tolerated (Plexoval II study, ACTRN12620000944932). As a secondary objective, biological activity in the context of wound healing rate was assessed. In this cohort of healthy participants, in which the wound bed would not be expected to be deficient in the bioactive cargo that pEVs carry, all wounds healed rapidly and completely and no difference in time to wound closure of the treated and untreated wounds was observed at the single dose tested. The outcomes of this study evidence that pEVs manufactured through the LEAP process can be injected safely in humans as a potential wound healing treatment, and warrant further study in clinical trials designed expressly to assess therapeutic efficacy in patients with delayed or disrupted wound healing.

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The complement system is crucial to the innate immune system. It has the function of destroying pathogens by activating the classical, alternative, and lectin pathways. The complement system is important in nervous system diseases such as cerebrovascular and neurodegenerative diseases. Activation of the complement system involves a series of intercellular signaling and cascade reactions. However, research on the source and transport mechanisms of the complement system in neurological diseases is still in its infancy. Studies have increasingly found that extracellular vesicles (EVs), a classic intercellular communication paradigm, may play a role in complement signaling disorders. Here, we systematically review the EV-mediated activation of complement pathways in different neurological diseases. We also discuss the prospect of EVs as future immunotherapy targets.

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Osteoarthritis (OA) is a disabling disease with significant morbidity worldwide. OA attacks the large synovial joint, including the peripheral joints and temporomandibular joint (TMJ). As a representative of peripheral joint OA, knee OA shares similar symptoms with TMJ OA. However, these two joints also display differences based on their distinct development, anatomy, and physiology. Extracellular vesicles (EVs) are phospholipid bilayer nanoparticles, including exosomes, microvesicles, and apoptotic bodies. EVs contain proteins, lipids, DNA, micro-RNA, and mRNA that regulate tissue homeostasis and cell-to-cell communication, which play an essential role in the progression and treatment of OA. They are likely to partake in mechanical response, extracellular matrix degradation, and inflammatory regulation during OA. More evidence has shown that synovial fluid and synovium-derived EVs may serve as OA biomarkers. More importantly, mesenchymal stem cell-derived EV shows a therapeutic effect on OA. However, the different function of EVs in these two joints is largely unknown based on their distinct biological characteristic. Here, we reviewed the effects of EVs in OA progression and compared the difference between the knee joint and TMJ, and summarized their potential therapeutic role in the treatment of OA.

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Mesenchymal stromal cells (MSCs) have been utilized in cell therapy for various diseases. Recent studies have demonstrated that extracellular vesicles (EVs) released by MSCs play an important role in their therapeutic activities. EVs contain a variety of bioactive molecules such as proteins, messenger RNAs (mRNAs), and micro RNAs (miRNAs) and modify the function of the recipient cells by transferring these molecules. Despite the promising potential of EV therapy as a substitute for MSC therapy, there are challenges that need to be addressed for the clinical success of EV therapy. EV quality has been shown to vary from batch to batch and preparation to preparation. As the consistency and reproducibility of therapeutic effects rely on the quality of EVs, it is necessary to establish techniques to manufacture scalable amounts of EVs with the same quality. In this manuscript, we discuss the potential factors that affect EV quality. We then introduce pre-clinical studies of EV therapy for bone/cartilage diseases such as osteoarthritis, rheumatoid arthritis, and osteoporosis.

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Extracellular vesicles (EVs) derived from the secretome of human mesenchymal stromal cells (MSC) contain numerous factors that are known to exert anti-inflammatory effects. MSC-EVs may serve as promising cell-based therapeutics for the inner ear to attenuate inflammation-based side effects from cochlear implantation which represents an unmet clinical need. In an individual treatment performed on a 'named patient basis', we intraoperatively applied allogeneic umbilical cord-derived MSC-EVs (UC-MSC-EVs) produced according to good manufacturing practice. A 55-year-old patient suffering from Menière's disease was treated with intracochlear delivery of EVs prior to the insertion of a cochlear implant. This first-in-human use of UC-MSC-EVs demonstrates the feasibility of this novel adjuvant therapeutic approach. The safety and efficacy of intracochlear EV-application to attenuate side effects of cochlea implants have to be determined in controlled clinical trials.

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SARS-CoV-2 entry is mediated by binding of the spike protein (S) to the surface receptor ACE2 and subsequent priming by host TMPRSS2 allowing membrane fusion. Here, we produced extracellular vesicles (EVs) exposing ACE2 and demonstrate that ACE2-EVs are efficient decoys for SARS-CoV-2 S protein-containing lentivirus. Reduction of infectivity positively correlates with the level of ACE2, is much more efficient than with soluble ACE2 and further enhanced by the inclusion of TMPRSS2.

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