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Extracellular vesicles (EVs) are intensively investigated for their therapeutic potential and application as drug delivery vehicle. A broad perception of favourable safety profiles and low immunogenicity make EVs an attractive alternative to synthetic nanoparticles. We recently showed that repeated intravenous administration of human cell-derived EVs into pig-tailed macaques unexpectedly elicited antibody responses after three or more injections. This coincided with decreasing EV circulation time, and may thus hamper successful EV-mediated cargo delivery into tissues. Here, we share the custom ELISA protocol that we used to measure such antibody responses. This protocol may help other researchers evaluate immune responses to EV-based therapies in preclinical studies., Competing Interests: KWW is or has been an advisory board member of ShiftBio, Exopharm, NeuroDex, NovaDip, and ReNeuron; holds NeuroDex options; privately consults as Kenneth Witwer Consulting; and has a sponsored research agreement with Ionis Pharmaceuticals., (© 2024 The Authors. Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

The 'QuantitatEVs: multiscale analyses, from bulk to single vesicle' workshop aimed to discuss quantitative strategies and harmonized wet and computational approaches toward the comprehensive analysis of extracellular vesicles (EVs) from bulk to single vesicle analyses with a special focus on emerging technologies. The workshop covered the key issues in the quantitative analysis of different EV-associated molecular components and EV biophysical features, which are considered the core of EV-associated biomarker discovery and validation for their clinical translation. The in-person-only workshop was held in Trento, Italy, from January 31 st to February 2 nd , 2023, and continued in Milan on February 3 rd with "Next Generation EVs", a satellite event dedicated to early career researchers (ECR). This report summarizes the main topics and outcomes of the workshop., Competing Interests: Conflicts of interest: The authors declare no conflict of interest.

Associations between plasma membrane blebbing and metastatic progression have been widely reported. There are also reports of increased extracellular vesicle release from cancer cells. Yet the ties between these closely related phenomena are incompletely understood. In this commentary, we remark on a recent finding on cellular membrane blebs in melanoma signaling. We discuss possible implications for cancer biology and draw parallels to knowns and unknowns in the relationships of extracellular vesicles and cancer progression.

Extracellular vesicles (EVs) large-scale production is a crucial point for the translation of EVs from discovery to application of EV-based products. In October 2021, the International Society for Extracellular Vesicles (ISEV), along with support by the FET-OPEN projects, "The Extracellular Vesicle Foundry" (evFOUNDRY) and "Extracellular vesicles from a natural source for tailor-made nanomaterials" (VES4US), organized a workshop entitled "massivEVs" to discuss the potential challenges for translation of EV-based products. This report gives an overview of the topics discussed during "massivEVs", the most important points raised, and the points of consensus reached after discussion among academia and industry representatives. Overall, the review of the existing EV manufacturing, upscaling challenges and directions for their resolution highlighted in the workshop painted an optimistic future for the expanding EV field., Competing Interests: No potential conflict of interest was reported by the authors., (© 2022 The Authors. Journal of Extracellular Biology published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Extracellular vesicles (EVs) have potential in disease treatment since they can be loaded with therapeutic molecules and engineered for retention by specific tissues. However, questions remain on optimal dosing, administration, and pharmacokinetics. Previous studies have addressed biodistribution and pharmacokinetics in rodents, but little evidence is available for larger animals. Here, we investigated the pharmacokinetics and biodistribution of Expi293F-derived EVs labelled with a highly sensitive nanoluciferase reporter (palmGRET) in a non-human primate model (Macaca nemestrina), comparing intravenous (IV) and intranasal (IN) administration over a 125-fold dose range. We report that EVs administered IV had longer circulation times in plasma than previously reported in mice and were detectable in cerebrospinal fluid (CSF) after 30-60 minutes. EV association with PBMCs, especially B-cells, was observed as early as one minute post-administration. EVs were detected in liver and spleen within one hour of IV administration. However, IN delivery was minimal, suggesting that pretreatment approaches may be needed in large animals. Furthermore, EV circulation times strongly decreased after repeated IV administration, possibly due to immune responses and with clear implications for xenogeneic EV-based therapeutics. We hope that our findings from this baseline study in macaques will help to inform future research and therapeutic development of EVs., Competing Interests: Conflict of interest The authors report no conflicts of interest.

When released into biological fluids like blood or saliva, brain extracellular vesicles (EVs) might provide a window into otherwise inaccessible tissue, contributing useful biomarkers of neurodegenerative and other central nervous system (CNS) diseases. To enrich for brain EVs in the periphery, however, cell-specific EV surface markers are needed. The protein that has been used most frequently to obtain EVs of putative neuronal origin is the transmembrane L1 cell adhesion molecule (L1CAM/CD171). In this systematic review, we examine the existing literature on L1CAM and EVs, including investigations of both neurodegenerative disease and cancer through the lens of the minimal information for studies of EVs (MISEV), specifically in the domains of nomenclature usage, EV sources, and EV separation and characterization. Although numerous studies have reported L1CAM-associated biomarker signatures that correlate with disease, interpretation of these results is complicated since L1CAM expression is not restricted to neurons and is also upregulated during cancer progression. A recent study has suggested that L1CAM epitopes are present in biofluids mostly or entirely as cleaved, soluble protein. Our findings on practices and trends in L1CAM-mediated EV separation, enrichment, and characterization yield insights that may assist with interpreting results, evaluating rigor, and suggesting avenues for further exploration., Competing Interests: CONFLICT OF INTEREST KWW is a member of the advisory board of NeuroDex, Inc.