Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

Extracellular vesicles for delivering therapeutic agents in ischemia/reperfusion injury

Ischemia/reperfusion(I/R)injury ismarked by the restriction and subsequent restoration of blood supply to an organ.This process can exacerbate the initial tissue damage,leading to further disorders,disability,and even death.Extracellular vesicles(EVs)are crucial in cell communication by releasing cargo that regulates the physiological state of recipient cells.The development of EVs presents a novel avenue for delivering therapeutic agents in I/R therapy.The therapeutic potential of EVs derived from stem cells,endothelial cells,and plasma in I/R injury has been actively investigated.Therefore,this review aims to provide an overview of the pathological process of I/R injury and the biophysical properties of EVs.We noted that EVs serve as nontoxic,flexible,and multifunctional carriers for delivering therapeutic agents capable of intervening in I/R injury progression.The therapeutic efficacy of EVs can be enhanced through various engineering strategies.Improving the tropism of EVs via surface modification and modulating their contents via preconditioning are widely investigated in preclinical studies.Finally,we summarize the challenges in the production and delivery of EV-based therapy in I/R injury and discuss how it can advance.This review will encourage further exploration in developing efficient EV-based delivery systems for I/R treatment.

Engineered extracellular vesicles:Regulating the crosstalk between the skeleton and immune system

Osteoimmunology has gained momentum in recent years,focusing on the crosstalk between the skeleton and the immune system.Extracellular vesicles(EVs)are nanoscale vesicles that are potential candidates for cell-free tissue regeneration strategies.They may be used for repairing damaged tissues and regulating the body’s immune system and bone-related metabolic activities.Because of the ability of EVs to deliver bioactive signals and mediate intercellular communication,they can decipher the complex mechanisms of interaction within the“osteoimmune system”at the molecular level.To address the lack of targeting ability caused by vesicle heterogeneity in the clinical applications of EVs,these nanoscopical entities may be modified by bioengineering techniques to optimize the interaction between bone repair and immunomodulation for improving treatment efficacy,specificity and safety.In the present review,the endogenous properties that make EVs natural delivery agents are outlined.Properties that may be improved by bioengineering are highlighted.The therapeutic applications of EVs in the rehabilitation of bone defects are discussed.The opportunities and challenges that need to be addressed for translating this field of research into clinical practice are brought into perspectives.

Extracellular vesicles modulate key signalling pathways in refractory wound healing

Chronic wounds are wounds that cannot heal properly due to various factors,such as underlying diseases,infection or reinjury,and improper healing of skin wounds and ulcers can cause a serious economic burden.Numerous studies have shown that extracellular vesicles(EVs)derived from stem/progenitor cells promote wound healing,reduce scar formation and have significant advantages over traditional treatment methods.EVs are membranous particles that carry various bioactive molecules from their cellular origins,such as cytokines,nucleic acids,enzymes,lipids and proteins.EVs can mediate cell-to-cell communication and modulate various physiological processes,such as cell differentiation,angiogenesis,immune response and tissue remodelling.In this review,we summarize the recent advances in EV-based wound healing,focusing on the signalling pathways that are regulated by EVs and their cargos.We discuss how EVs derived from different types of stem/progenitor cells can promote wound healing and reduce scar formation by modulating the Wnt/β-catenin,phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,vascular endothelial growth factor,transforming growth factorβand JAK-STAT pathways.Moreover,we also highlight the challenges and opportunities for engineering or modifying EVs to enhance their efficacy and specificity for wound healing.

Reprogramming macrophages via immune cell mobilized hydrogel microspheres for osteoarthritis treatments

Regulating macrophage activation precisely is crucial in treating chronic inflammation in osteoarthritis(OA).However,the stable pro-inflammatory state and deep distribution of macrophages in vivo pose a great challenge to treatment.In this study,inspired by the innate immune,immune cell mobilized hydrogel microspheres were constructed by microfluidic methods and load chemokines,macrophage antibodies and engineered cell membrane vesicles(sEVs)via covalent and non-covalent junctions.The immune cell mobilized hydrogel microspheres,based on a mixture of streptavidin grafted hyaluronic acid methacrylate(HAMA-SA)and Chondroitin sulfate methacrylate(ChSMA)microspheres(HCM),can recruit,capture and reprogram proinflammatory macrophages in the joint cavity to improve the joint inflammatory microenvironment.In vitro experiments demonstrated that immune cell mobilized hydrogel microspheres had excellent macrophage recruitment,capture,and reprogramming abilities.Pro-inflammatory macrophages can be transformed into anti-inflammatory macrophages with an efficiency of 88.5%.Animal experiments also revealed significant reduction in synovial inflammation and cartilage matrix degradation of OA.Therefore,the immune cell mobilized hydrogel microspheres may be an effective treatment of OA inflammation for the future.