Exploring the clinical transition of engineered exosomes designed for intracellular delivery of therapeutic proteins.

Extracellular vesicles, particularly exosomes, have emerged as promising drug delivery systems owing to their unique advantages, such as biocompatibility, immune tolerability, and target specificity. Various engineering strategies have been implemented to harness these innate qualities, with a focus on enhancing the pharmacokinetic and pharmacodynamic properties of exosomes via payload loading and surface engineering for active targeting. This concise review outlines the challenges in the development of exosomes as drug carriers and offers insights into strategies for their effective clinical translation. We also highlight preclinical studies that have successfully employed anti-inflammatory exosomes and suggest future directions for exosome therapeutics. These advancements underscore the potential for integrating exosome-based therapies into clinical practice, heralding promise for future medical interventions.

Effects of NF-κB Inhibitor on Sepsis Depend on the Severity and Phase of the Animal Sepsis Model.

Hyperinflammation occurs in sepsis, especially in the early phase, and it could have both positive and negative effects on sepsis. Previously, we showed that a new concept of NF-κB inhibitor, exosome-based super-repressor IκBα (Exo-srIκB) delivery, has a beneficial effect on sepsis. Here, we further investigate the therapeutic effects of Exo-srIκB at different severities and phases of sepsis using an animal polymicrobial intra-abdominal infection model. We used a rat model of fecal slurry polymicrobial sepsis. First, we determined the survival effects of Exo-srIκB on sepsis according to the severity. We used two different severities of the animal sepsis model. The severe model had a mortality rate of over 50%. The mild/moderate model had a less than 30% mortality rate. Second, we administered the Exo-srIκB at various time points (1 h, 6 h, and 24 h after fecal slurry administration) to determine the therapeutic effect of Exo-srIκB at different phases of sepsis. Lastly, we determined the effects of the Exo-srIκB on cytokine production, arterial blood gas, electrolyte, and lactate. The survival gain was statistically significant in the severe sepsis model when Exo-srIκB was administered 6 h after sepsis. Interleukin 6 and interleukin-10 were significantly decreased in the kidney when administered with Exo-srIκB. The laboratory data showed that lactate, glucose, and potassium levels were significantly lowered in the NF-κB inhibitor group. In conclusion, Exo-srIκB exhibited a beneficial therapeutic effect when administered 6 h post fecal slurry administration in a severe sepsis model.

Exosome-mediated delivery of super-repressor IκBα alleviates inflammation and joint damages in rheumatoid arthritis.

BACKGROUND: This study aims to investigate the potential anti-inflammatory effects of exosomes engineered to carry super-repressor IκB (Exo-srIκB), an exosome-based NF-κB inhibitor, in the context of RA. METHODS: Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected from patients diagnosed with RA and treated with Exo-srIκB to test the therapeutic potential. Flow cytometry analysis was performed to assess the production of inflammatory cytokines (IL-17A and GM-CSF) by the cells. ELISA was utilized to measure the levels of TNF-α, IL-17A, IL-6, and GM-CSF. Arthritis was induced in SKG mice by intraperitoneal injection of curdlan. DBA/1 J mice were used in collagen-induced arthritis (CIA) experiments. After the development of arthritis, mice were injected with either Exo-Naïve (control exosome) or Exo-srIκB. Arthritis scores were recorded biweekly, and histological observations of the ankle joint were conducted using H&E and safranin-O staining. Additionally, bone erosion was evaluated using micro-CT imaging. RESULTS: In the ex vivo study involving human PBMCs and SFMCs, treatment with Exo-srIκB demonstrated a notable reduction in inflammatory cytokines. Furthermore, in both the SKG and CIA models, Exo-srIκB treatment exhibited significant reductions in inflammation, cartilage destruction, and bone erosion within the joint tissues when compared to the Exo-Naive control group. Additionally, the radiographic score assessed through microCT showed a significant decrease compared to the Exo-Naive control group. CONCLUSION: Overall, these findings suggest that Exo-srIκB possesses anti-inflammatory properties in human RA cells and animal models, making it a promising therapeutic candidate for the treatment of RA.

Efficacy of Allogeneic and Xenogeneic Exosomes for the Treatment of Canine Atopic Dermatitis: A Pilot Study.

Canine atopic dermatitis (CAD) is a genetically predisposed inflammatory pruritic skin disease. The available treatments for CAD have several adverse effects and vary in efficacy, indicating the need for the development of improved treatments. In this study, we aimed to elucidate the therapeutic effects of allogeneic and xenogeneic exosomes on CAD. Six laboratory beagle dogs with CAD were randomly assigned to three treatment groups: control, canine exosome (cExos), or human exosome (hExos) groups. Dogs in the cExos and hExos groups were intravenously administered 1.5 mL of cExos (5 × 1010) and hExos (7.5 × 1011) solutions, respectively, while those in the control group were administered 1.5 mL of normal saline three times per week for 4 weeks. Skin lesion score and transepidermal water loss decreased in cExos and hExos groups compared with those in the control group. The exosome treatments decreased the serum levels of inflammatory cytokines (interferon-γ, interleukin-2, interleukin-4, interleukin-12, interleukin-13, and interleukin-31) but increased those of anti-inflammatory cytokines (interleukin-10 and transforming growth factor-ß), indicating the immunomodulatory effect of exosomes. Skin microbiome analysis revealed that the exosome treatments alleviated skin bacterial dysbiosis. These results suggest that allogeneic and xenogeneic exosome therapy may alleviate CAD in dogs.

Can a natural singing voice be enhanced through digital processing? Implications of voice training and vocology in singers / ¿Se puede mejorar una voz de canto natural a través del procesamiento digital? Implicaciones del entrenamiento de la voz y la vocología en cantantes

Introduction. The traditional way of facilitating a good singing voice has been achieved through rigorous voice training. In the modern days, however, there are some aspects of the singing voice that can be enhanced through digital processing. Although in the past, the frequency or intensity manipulations had to be achieved through the various singing techniques of the singer, technology today allows the singing voice to be enhanced from the instruments within recording studios. In es-sence, the traditional voice pedagogy and the evolution of digital audio processing both strive to achieve a better quality of the singing voice, but with different methods. Nevertheless, the major aspects of how the singing voice can be manipulated are not communicated among the professionals in each field.Objective. This paper offers insights as to how the quality of the singing voice can be changed physiologically through the traditional ways of voice training, and also digitally through various instruments that are now available in recording studios.Reflection. The ways in which singers train their voice must be mediated with the audio technology that is available today. Although there are aspects in which the digi-tal technology can aid the singer's voice, there remain areas in which the singers must train their singing system in a physiological level to produce a better singing voice

Introducción. La forma tradicional de facilitar una buena voz para cantar se ha lo-grado mediante un riguroso entrenamiento de la voz. Sin embargo, en la actualidad, existen aspectos de la voz cantada que pueden mejorarse mediante el procesamiento digital. Aunque en el pasado las manipulaciones de frecuencia o intensidad tenían que lograrse a través de las diversas técnicas de canto del cantante, la tecnología actual permite ahora mejorar la voz del canto desde los instrumentos dentro de los estudios de grabación. En esencia, la pedagogía de la voz tradicional y la evolución del procesamiento de audio digital se esfuerzan por lograr una mejor calidad de la voz cantada, pero con métodos diferentes. No obstante, los principales aspectos de cómo se puede manipular la voz cantada no se comunican entre los profesionales de cada campo respectivo. Objetivo. Este artículo ofrece información sobre cómo la calidad de la voz cantada se puede cambiar fisiológicamente a través de las formas tradicionales del entrena-miento de la voz, y también digitalmente a través de varios instrumentos que ahora están disponibles en los estudios de grabación. Reflexión. Las formas en que los cantantes entrenan su voz deben estar mediadas por la tecnología de audio que está disponible en la actualidad. Aunque hay aspectos en los que la tecnología digital puede ayudar a la voz del cantante, quedan áreas en las que los cantantes deben entrenar su sistema de canto a nivel fisiológico para pro-ducir una mejor voz al cantar.