The native role of extracellular vesicles (EVs) in mediating the transfer of biomolecules between cells has raised the possibility to use them as therapeutic vehicles. The development of therapies based on EVs is now expanding rapidly; here we will describe the current knowledge on different key points regarding the use of EVs in a clinical setting. These points are related to cell sources of EVs, isolation, storage, and delivery methods, as well as modifications to the releasing cells for improved production of EVs. Finally, we will depict the application of EVs therapies in clinical trials, considering the impact of the COVID-19 pandemic on the development of these therapies, pointing out that although it is a promising therapy for human diseases, we are still in the initial phase of its application to patients.

The mitochondria play a crucial role in cellular metabolism, reactive oxygen species (ROS) production, and apoptosis. Aberrant mitochondria can cause severe damage to the cells, which have established a tight quality control for the mitochondria. This process avoids the accumulation of damaged mitochondria and can lead to the release of mitochondrial constituents to the extracellular milieu through mitochondrial extracellular vesicles (MitoEVs). These MitoEVs carry mtDNA, rRNA, tRNA, and protein complexes of the respiratory chain, and the largest MitoEVs can even transport whole mitochondria. Macrophages ultimately engulf these MitoEVs to undergo outsourced mitophagy. Recently, it has been reported that MitoEVs can also contain healthy mitochondria, whose function seems to be the rescue of stressed cells by restoring the loss of mitochondrial function. This mitochondrial transfer has opened the field of their use as potential disease biomarkers and therapeutic tools. This review describes this new EVs-mediated transfer of the mitochondria and the current application of MitoEVs in the clinical environment.

Aging is associated with an alteration of intercellular communication. These changes in the extracellular environment contribute to the aging phenotype and have been linked to different aging-related diseases. Extracellular vesicles (EVs) are factors that mediate the transmission of signaling molecules between cells. In the aging field, these EVs have been shown to regulate important aging processes, such as oxidative stress or senescence, both in vivo and in vitro. EVs from healthy cells, particularly those coming from stem cells (SCs), have been described as potential effectors of the regenerative potential of SCs. Many studies with different animal models have shown promising results in the field of regenerative medicine. EVs are now viewed as a potential cell-free therapy for tissue damage and several diseases. Here we propose EVs as regulators of the aging process, with an important role in tissue regeneration and a raising therapy for age-related diseases.

The aim of this study was to evaluate the association of arterial hyperoxemia with neurological outcomes and mortality in adults with acute brain injury (ABI). Six electronic databases, including MEDLINE, Embase and online registers of clinical trials, were systematically searched from inception to June 1 st, 2024. Studies comparing the effects of hyperoxemia versus no hyperoxemia on outcomes of hospitalized adult patients with ABI-related conditions (e.g. traumatic brain injury, post-cardiac arrest, subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke) were included according to PRISMA guidelines. Data were pooled using a random-effects model for unadjusted and covariate-adjusted odds ratios. The primary outcome was poor neurological outcome as defined by each individual study, and the secondary outcome was all-cause mortality. Subgroup analyses were conducted based on principal diagnosis, timing of outcome measures, oxygenation thresholds, among other factors. Meta-regression was applied to identify sources of heterogeneity. After 7,849 nonduplicated records were screened, 66 studies fulfilled eligibility criteria for systematic review. The meta-analysis including 24 studies (16,635 patients) revealed that patients with hyperoxemia are 1.29 times more likely to develop poor neurological outcomes (unadjusted OR, 1.295; 95% Confidence Interval, CI 1.040–1.616) compared with those with no hyperoxemia, particularly in subarachnoid hemorrhage and ischemic stroke subgroups. The meta-analysis including 35 studies (98,207 patients) revealed that all-cause mortality is 1.13 times more likely (OR 1.13; 95% CI 1.002–1.282) in patients with hyperoxemia compared with no hyperoxemia. In our study we found that hyperoxemia is significantly associated with an increased risk of poor neurological outcomes and mortality in patients with acute brain injury compared to those with no hyperoxemia. Our results suggest the importance of carefully adjusting oxygenation strategies in neurocritical ICUs.

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply inter-related and act together to drive the aging process. Altered intercellular communication is particularly relevant since it explains how damage at the cellular level translates into age-related loss of function at the organismal level. As the main effectors of intercellular communication, extracellular vesicles (EVs) might play a key role in the aggravation or mitigation of the hallmarks of aging. This review aims to summarize this role and to provide context for the multiple emerging EV-based gerotherapeutic strategies that are currently under study.

Delayed neurocognitive recovery and postoperative neurocognitive disorders are major complications of surgery, hospitalization, and anesthesia that are receiving increasing attention. Their incidence is reported to be 10–80% after cardiac surgery and 10–26% after non-cardiac surgery. Some of the risk factors include advanced age, level of education, history of diabetes mellitus, malnutrition, perioperative hyperglycemia, depth of anesthesia, blood pressure fluctuation during surgery, chronic respiratory diseases, etc. Scientific evidence suggests a causal association between anesthesia and delayed neurocognitive recovery or postoperative neurocognitive disorders, and various pathophysiological mechanisms have been proposed: mitochondrial dysfunction, neuroinflammation, increase in tau protein phosphorylation, accumulation of amyloid-β protein, etc. Insulin receptors in the central nervous system have a non-metabolic role and act through a neuromodulator-like action, while an interaction between anesthetics and central nervous system insulin receptors might contribute to anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders. Acute or chronic intranasal insulin administration, which has no influence on the blood glucose concentration, appears to improve working memory, verbal fluency, attention, recognition of objects, etc., in animal models, cognitively healthy humans, and memory-impaired patients by restoring the insulin receptor signaling pathway, attenuating anesthesia-induced tau protein hyperphosphorylation, etc. The aim of this review is to report preclinical and clinical evidence of the implication of intranasal insulin for preventing changes in the brain molecular pattern and/or neurobehavioral impairment, which influence anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders.