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.

Glioblastoma remain one of the deadliest malignant tumors in the central nervous system, largely due to their aggressiveness, high degree of heterogeneity, and the protective barrier of the blood-brain barrier (BBB). Conventional therapies including surgery, chemotherapy and radiotherapy often fail to improve patient prognosis due to limited drug penetration and non-specific toxicity. We then present recent advances in biomimetic nanodelivery systems, focusing on cell membrane coatings, nanoenzymes, and exosome-based carriers. By mimicking endogenous biological functions, these systems demonstrate improved immune evasion, enhanced BBB traversal, and selective drug release within the tumor microenvironment. Nevertheless, we acknowledge unresolved bottlenecks related to large-scale production, stability, and the intricacies of regulatory compliance. Looking forward, we propose an interdisciplinary roadmap that combines materials engineering, cellular biology, and clinical expertise. Through this collaborative approach, this work aims to optimize biomimetic nanodelivery for glioma therapy and ultimately improve patient outcomes.

Ischemic stroke is a secondary cause of mortality worldwide, imposing considerable medical and economic burdens on society. Extracellular vesicles, serving as natural nano-carriers for drug delivery, exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke. However, the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency. By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles, their delivery efficacy may be greatly improved. Furthermore, previous studies have indicated that microvesicles, a subset of large-sized extracellular vesicles, can transport mitochondria to neighboring cells, thereby aiding in the restoration of mitochondrial function post-ischemic stroke. Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components, such as proteins or deoxyribonucleic acid, or their sub-components, for extracellular vesicle-based ischemic stroke therapy. In this review, we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies. Given the complex facets of treating ischemic stroke, we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process. Moreover, given the burgeoning interest in mitochondrial delivery, we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Despite the increasing global prevalence of neurological disorders, the development of nanoparticle (NP) technologies for brain-targeted therapies confronts considerable challenges. One of the key obstacles in treating brain diseases is the blood-brain barrier (BBB), which restricts the penetration of NP-based therapies into the brain. To address this issue, NPs can be installed with specific ligands or bioengineered to boost their precision and efficacy in targeting brain-diseased cells by navigating across the BBB, ultimately improving patient treatment outcomes. At the outset of this review, we highlighted the critical role of ligand-functionalized or bioengineered NPs in treating brain diseases from a clinical perspective. We then identified the key obstacles and challenges NPs encounter during brain delivery, including immune clearance, capture by the reticuloendothelial system (RES), the BBB, and the complex post-BBB microenvironment. Following this, we overviewed the recent progress in NPs engineering, focusing on ligand-functionalization or bionic designs to enable active BBB transcytosis and targeted delivery to brain-diseased cells. Lastly, we summarized the critical challenges hindering clinical translation, including scalability issues and off-target effects, while outlining future opportunities for designing cutting-edge brain delivery technologies.

Intracellular Staphylococcus aureus is associated with recurrent infections and antibiotic resistance. Conventional antibiotics are ineffective against such intracellular bacterial pathogens, which calls for exploration of new approaches to treat these infections. Here, we report the development of pathogen-targeting biomineralized bacterial outer membrane vesicle (OMV) for targeted antibiotic delivery and eradicating both intracellular and extracellular S. aureus. These OMVs were derived from E. coli, and chemically modified with hydroxamate-type siderophore to target the intracellular S. aureus. The surface of OMV was coated with pH-sensitive calcium carbonate (CaCO3) to target the infection microenvironment. The CaCO3-coated siderophore-OMV (SOMV@CaCO3) was loaded with the antimicrobial drugs lysostaphin (Lsn) and mupirocin (Mup) (Lsn-SOMV@CaCO3-Mup) and administration of these OMVs resulted in effective eradication of both extracellular and intracellular S. aureus. Thus, Lsn-SOMV@CaCO3-Mup provides a novel and promising strategy for the treatment of invasive S. aureus infections.

Astrocytes can be reacted to "reactive astrocytes" after ischemia-reperfusion injury, in which A1 phenotype causes neuronal and oligodendrocyte death, whereas the A2 phenotype exerts neuroprotective effects, thus regulating reactive astrocyte to A2 type is a potential target for stroke therapy. Lcn2 level is highly associated with the phenotypic polarization of astrocytes. We found that silencing the Lcn2 gene by adeno-associated virus (AAV)-Lcn2 shRNA adenovirus resulted in a dramatic decrease in A1-type astrocytes and increase in A2 astrocytes in MCAO mice. Hence, a nanoplatform was developed for stroke therapy by inhibiting Lcn2. This system was fabricated by N-acetyl Pro-Gly-Pro peptide-decorated rod-shaped poly (lactic-co-glycolic acid) nanoparticles loading with rolipram (AP@R). The nanodrug can be efficiently taken up by neutrophils simultaneously through morphology-mediated passive targeting and Cxcr2 receptor-mediated active targeting, subsequently crossing the blood-brain barrier (BBB) by hitchhiking neutrophils. When accumulating at the brain parenchyma, the released rolipram can inhibit the Lcn2 level, thereby reversing the astrocyte phenotype to alleviate neuroinflammation and promote BBB repair. This work provides a new strategy for treating ischemic stroke.

Cancer remains one of the most devastating diseases, severely affecting public health and contributing to economic instability. Researchers worldwide are dedicated to developing effective therapeutics to target cancer cells. One promising strategy involves inducing cellular senescence, a complex state in which cells exit the cell cycle. Senescence has profound effects on both physiological and pathological processes, influencing cellular systems through secreted factors that affect surrounding and distant cells. Among these factors are exosomes, small extracellular vesicles that play crucial roles in cellular communication, development, and defense, and can contribute to pathological conditions. Recently, there has been increasing interest in engineering exosomes as precise drug delivery vehicles, capable of targeting specific cells or intracellular components. Studies have emphasized the significant role of exosomes from senescent cells in cancer progression and therapy. Notably, chemotherapeutic agents can alter the tumor microenvironment, induce senescence, and trigger immune responses through exosome-mediated cargo transfer. This review explores the intricate relationship between cellular senescence, exosomes, and cancer, examining how different therapeutics can eliminate cancer cells or promote drug resistance. It also investigates the molecular mechanisms and signaling pathways driving these processes, highlighting current challenges and proposing future perspectives to uncover new therapeutic strategies for cancer treatment.

With the ever-increasing burden of urological diseases, the need for developing novel imaging biomarkers and therapeutics to manage these disorders has never been greater. Extracellular vesicles (EVs) are natural membranous nanoparticles and widely applied in both diagnostics and therapeutics for many diseases. A growing body of research has demonstrated that EVs can be engineered to enhance their efficiency, specificity, and safety. We systematically examine the strategies for achieving targeted delivery of EVs as well as the techniques for engineering them in this review, with a particular emphasis on cargo loading and transportation. Additionally, this review highlights and summarizes the wide range of imaging biomarkers and therapeutic applications of engineered EVs in the context of urological diseases, emphasizing the potential applications in urological malignancy and kidney diseases.

Ischemic stroke (IS), characterized by acute cerebral vascular occlusion and narrow therapeutic windows, poses formidable clinical challenges due to the blood-brain barrier (BBB) restriction, reperfusion injury risks, and limited efficacy of conventional thrombolytic therapies. These hurdles necessitate advanced delivery systems capable of precise BBB penetration, remodeled circulation, and neuroprotection. Proteins and peptides emerge as universal biomaterials for constructing nano-delivery platforms, leveraging their biocompatibility, biodegradability, low toxicity, and receptor-specific targeting. This review systematically explores protein-based nanomaterials in stroke intervention, emphasizing material selection, fabrication strategies, and therapeutic applications. Various structural proteins are analyzed for their unique advantages in carrier design, while peptide modifications are highlighted for enhancing targeted delivery. Critical fabrication techniques are discussed to balance stability and functionality. Furthermore, the applications of protein-based nanomaterials in IS therapy are summarized. Advanced preparation and application of protein-based nanomaterials, from delivery vehicles to ligand modification, potentially prolong the therapeutic window for IS and provide effective neuroprotection.

Extracellular vesicles (EVs) are widely explored as vehicles for delivering therapeutic or experimental cargo to cardiomyocytes. Efforts to improve EV bioavailability in the heart, and reduce their off-target actions, require screening methods that can replicate the physiological and anatomical barriers present in the myocardium. Additionally, discovery pipelines must exercise control over EV dosage and timing, and provide a means of assessing cargo incorporation into cardiomyocytes specifically. These criteria are not generally met by experiments on cultured cells or animals. Here, we present a Langendorff-heart discovery pipeline that combines the strengths of in vivo and in vitro approaches. Langendorff-mode perfusion enables controlled exposure of beating hearts to re-circulated EVs. Following perfusion, cardiomyocytes can be isolated enzymatically for analysis, such as imaging. We tested this discovery pipeline by functionalizing EVs with beta-blockers (atenolol, metoprolol) using click-chemistry and incorporating the fluorescent protein NeonGreen2 to track the fate of EV cargo. Fluorescence in cardiomyocytes, including their nuclear regions, increased after Langendorff-treatment with beta-blocker decorated EVs, but only if these contained NeonGreen2, implicating the fluorescent cargo as the source of signal. Superior binding efficacy of beta-blockers was confirmed by referencing to the substantially lower signals obtained using wild-type EVs or EVs presenting myomaker or myomixer proteins, motifs that modestly enrich cardiac EV uptake in mice. Our findings demonstrate successful cardiomyocyte targeting using EVs decorated with beta-receptor binders. We propose the Langendorff-perfused heart as an intermediate step, nested between in vitro characterisation and animal testing, in discovery pipelines for seeking improved EV designs for the heart.

Exosomes, nanoscale vesicles involved in intercellular communication, have garnered significant attention for their potential in drug delivery and therapeutic applications. This review provides a comparative analysis of mammalian-derived exosomes, particularly milk-derived exosomes, and plant-derived exosome-like nanoparticles (PDENs). It explores their biogenesis, bioactivities, and functional similarities, including their roles in cellular communication, immune modulation, and disease therapy. While milk-derived exosomes exhibit promising biocompatibility and stability for targeted delivery, PDENs offer distinct advantages, such as scalability and inherent bioactivities, derived from their plant sources. Despite similarities in their structure and cargo, PDENs differ in lipid composition and protein profiles, reflecting plant-specific functions. Emerging research highlights the therapeutic potential of PDENs in managing inflammation, oxidative stress, and other diseases, emphasizing their utility as functional food components and nanocarriers. However, challenges related to their chemical stability and large-scale production require further investigation. This review underscores the need for advanced studies to fully harness the potential of these natural nanocarriers in drug-delivery systems and therapeutic interventions.

Background The recent surge in research on extracellular vesicles has generated considerable interest in their clinical applications. Extracellular vesicles derived from mesenchymal stem cells (MSC-EV) have emerged as a promising cell-free therapy for chronic kidney disease (CKD), offering an alternative to traditional Mesenchymal stem/stromal cells (MSCs) in extracellular vesicle-based nanotherapeutics. However, challenges such as in vivo off-target effects and limited bioavailability have impeded the wider adoption of MSC-EV in clinical settings. Methods Arginyl-glycyl-aspartic acid peptide-modified MSC-EV (RGD-MSC-EV) were developed using a donor cell-assisted membrane modification strategy. The targeting capability and therapeutic efficacy of RGD-MSC-EV were thoroughly evaluated both in vitro and in vivo. Additionally, the mechanisms of RNA N6-methyladenosine (m6A) methylation-mediated angiogenesis were extensively investigated to elucidate how RGD-MSC-EV mitigates renal fibrosis. Results RGD-MSC-EV demonstrated exceptional targeted delivery efficiency, exhibiting optimal biodistribution and retention within the target tissue. This breakthrough positions them as significantly enhanced anti-fibrotic therapeutics. Notably, RGD-MSC-EV sustains the viability of renal peritubular capillary (PTCs) endothelial cells by transporting microRNA-126-5p (miR-126-5p) and modulating alkB homolog 5 (ALKBH5)-mediated m6A modification of SIRT1(Sirtuin 1), a crucial regulator in angiogenesis. By revitalizing endothelial cells and promoting microcirculation, this approach restored oxygen metabolism homeostasis, ultimately delaying fibrogenesis associated with CKD. Conclusions RGD-MSC-EV offers a feasible and effective strategy to alleviate renal interstitial fibrosis by restoring m6A and mitigating the loss of renal PTCs. STATEMENT OF SIGNIFICANCE: Chronic kidney disease (CKD) often leads to renal fibrosis, which worsens disease progression. This study introduces a novel strategy using engineered extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EV). By modifying these EVs with RGD peptides, we significantly enhance their targeting ability to hypoxic kidney tissues. The research reveals how these EVs deliver microRNA (miR-126-5p) to restore key molecular mechanisms, stabilizing SIRT1 expression through m6A RNA modifications. This approach promotes blood vessel health and delays fibrosis. Compared to current treatments, RGD-MSC-EV offers a safe, effective, and cell-free therapeutic alternative. These findings advance the understanding of EV-based therapies and their clinical potential, bridging basic research and real-world CKD treatment applications.

Heterotopic Ossification (HO), refers to pathological extra skeletal bone formation, and there are currently no reliable methods except surgery to reverse these unexpected calcified tissues. Apoptotic vesicles (ApoEVs) are membrane-bound vesicles released by apoptotic cells, which are involved in metabolism regulation and intercellular communication. Due to its superior trauma-healing ability, the hard palate mucosa is expected to become an essential resource for tissue engineering. This work presents a minimally invasive nanotherapy based on an engineered apoEV. Briefly, apoEVs were extracted from hard palate mucosa and engineered with bone-targeting peptide SDSSD to treat HO. This engineered apoEV not only can achieve directed localization of heterotopic bones but also has the compelling dual function of promoting osteoclastic differentiation while inhibiting osteogenic differentiation. The underlying mechanism involves the activation of Hippo and Notch pathways, as well as the regulation of pyrimidine metabolism. We envision that this engineered apoEV may be a feasible and effective strategy for reversing HO.

In the cardiovascular system, different types of cardiovascular cells can secrete specific exosomes and participate in the maintenance of cardiovascular function and the occurrence and development of diseases. Exosomes carry biologically active substances such as proteins and nucleic acids from cells of origin and can be used as biomarkers for disease diagnosis and prognosis assessment. In addition, exosome-mediated intercellular communication plays a key role in the occurrence and development of cardiovascular diseases and has become a potential therapeutic target. This article emphasizes the importance of understanding the mechanism of exosomes in cardiovascular diseases and systematically details the current understanding of exosomes as regulators of intercellular communication in cardiomyocytes, providing a basis for future research and therapeutic intervention.

Glioblastoma (GBM) poses a formidable challenge because of its high morbidity and mortality. The therapeutic efficacy of GBM is significantly hampered by the intricate blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Nanomaterial-based brain-targeted delivery systems have shown great potential for effectively delivering therapeutic agents for GBM treatment by overcoming the limitations of conventional drugs, such as poor BBB penetration, a short half-life, and low bioavailability. This review focuses on an in-depth analysis of the interplay between the BBB/BBTB and drug transport kinetics while analyzing innovative nanoparticle-mediated strategies for enhanced GBM treatment. Moreover, the delivery strategies of nanoparticle-based brain-targeted systems are emphasized, with particular attention given to biomimetic nanoparticles (BMNPs), whose unique advantages. The current challenges, translational potential, and future research directions in this rapidly evolving field are comprehensively discussed, highlighting advances in nanomaterial applications. This review aims to stimulate further research into GBM delivery systems, offering promising avenues for maximizing the therapeutic effects of gene drugs or chemotherapeutic agents in practical applications.

Post-stroke depression (PSD) is common among stroke survivors and negatively impacts recovery. Chaihu-Shugan-San (CSS), a traditional Chinese medicine, has shown therapeutic potential for mood disorders, particularly PSD. Recent studies suggest that CSS's effects may be mediated by exosomes, but the mechanisms remain unclear.

This study aimed to evaluate the therapeutic effects of CSS on PSD in mice and investigate the underlying mechanisms, particularly the role of exosomes.

Active compounds in CSS were identified from rat serum using liquid chromatography-mass spectrometry (LC-MS) and analyzed through network pharmacology. In vitro, an oxygen-glucose deprivation/reperfusion (OGD/R) BV2 microglia model was used to assess the effects of CSS-containing serum (CSS-S). Exosomes from OGD/R-treated BV2 microglia were isolated, labeled with PKH26, and analyzed using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). In vivo, a photothrombotic stroke (PT) model combined with chronic unpredictable mild stress (CUMS) was used to induce PSD in mice. Behavioral assessments and histological analysis were performed, along with immunofluorescence (IF), ELISA and q-PCR to measure key protein and miR-146 expression in the hippocampus.

CSS treatment significantly alleviated depressive-like behaviors in the PSD mouse model. Mice treated with high-dose CSS (4.2 g/kg) exhibited increased sucrose preference, reduced immobility in the tail suspension test (TST) and forced swimming test (FST), and enhanced exploratory activity in the open field test (OFT). Histological analysis demonstrated that CSS treatment improved brain tissue integrity, alleviating neuronal damage and reducing neuroinflammation. Exosome analysis revealed that CSS increased the expression of microglia-derived exosomes in the hippocampus, which were shown to carry miR-146. Further examination of miR-146 isoforms in the hippocampal tissue revealed significant changes: miR-146b-3p and miR-146a-5p were upregulated, while miR-146a-3p and miR-146b-5p were downregulated in PSD mice. Treatment with CSS reversed the altered miRNA expression, indicating a potential mechanism for its neuroprotective effects. Additionally, CSS treatment reduced the expression of inflammatory cytokines such as S100A8, IL1β, IL6, and TNF-α, while restoring the levels of angiogenic factors VEGFC and VEGFR3. ELISA measurements showed significant decreases in cyclic AMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) in PSD mice; high-dose CSS notably elevated CREB and BDNF levels and showed comparable effects to fluoxetine in restoring 5-HT and DA levels. Additionally, the calcium signaling pathway was implicated, with altered mRNA expressions of CaMKIIα, CREB, phosphorylated CREB (p-CREB), PDE4D, and BDNF, although fluoxetine demonstrated stronger modulatory effects than CSS.

CSS alleviates PSD in mice by modulating exosome-mediated signaling, particularly through the regulation of miR-146. The treatment reversed abnormal miRNA expression, reduced neuroinflammation, and improved synaptic function. These findings highlight CSS's potential as an effective therapeutic strategy for PSD by targeting exosome-mediated neuroprotection and miR-146 regulation.

The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods.

This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions.

By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.

Cerebral ischemia-reperfusion injury (CI/RI) is currently considered a significant factor affecting the prognosis of ischemic stroke. The blood-brain barrier (BBB) plays multiple roles in the treatment ofCI/RI. BBB leakage allows bloodborne toxins to exacerbate the stroke pathology. Yet as the physiological barrier that separates the blood from the brain, BBB also poses a significant obstacle to therapeutic drug delivery. Therefore, it is essential to consider both crossing and repairing the BBB in the process of the treatment of CI/RI. Leveraging the exceptional benefits of nanoparticles (NPs) for BBB penetration and targeted repair, numerous NPs are developed as promising drug delivery platforms. Considering the complex role of the BBB in CI/RI, this review delves into the strategies for designing NPs to cross the BBB, focusing on peptide-modified NPs, cell-mediated NPs, cell membrane-derived NPs, and BBB-modulating NPs. Additionally, it summarizes design strategies of NPs targeting endothelial cells (ECs), astrocytes, and those aimed at regulating the microenvironment to repair the BBB. On this basis, it reveals the prospects and challenges of NPs designed around the BBB in CI/RI treatment. And it highlights the need to combine BBB permeability promotion and BBB repair in nanoparticle strategies designed based on the BBB to achieve more effective treatment.

From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.

Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery. Therefore, there is an urgent need to develop new methods for the treatment of this condition. Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions. They have low immunogenicity, good stability, high delivery efficiency, and the ability to cross the blood-brain barrier. These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke. The rapid development of nanotechnology has advanced the application of engineered exosomes, which can effectively improve targeting ability, enhance therapeutic efficacy, and minimize the dosages needed. Advances in technology have also driven clinical translational research on exosomes. In this review, we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke, including their anti-inflammation, anti-apoptosis, autophagy-regulation, angiogenesis, neurogenesis, and glial scar formation reduction effects. However, it is worth noting that, despite their significant therapeutic potential, there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes. Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke. Ultimately, our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.

The advent of genome editing has kindled the hope to cure previously uncurable, life-threatening genetic diseases. However, whether this promise can be ultimately fulfilled depends on how efficiently gene editing agents can be delivered to therapeutically relevant cells. Over time, viruses have evolved into sophisticated, versatile, and biocompatible nanomachines that can be engineered to shuttle payloads to specific cell types. Despite the advances in safety and selectivity, the long-term expression of gene editing agents sustained by viral vectors remains a cause for concern. Cell-derived vesicles (CDVs) are gaining traction as elegant alternatives. CDVs encompass extracellular vesicles (EVs), a diverse set of intrinsically biocompatible and low-immunogenic membranous nanoparticles, and virus-like particles (VLPs), bioparticles with virus-like scaffold and envelope structures, but devoid of genetic material. Both EVs and VLPs can efficiently deliver ribonucleoprotein cargo to the target cell cytoplasm, ensuring that the editing machinery is only transiently active in the cell and thereby increasing its safety. In this review, we explore the natural diversity of CDVs and their potential as delivery vectors for the clustered regularly interspaced short palindromic repeats (CRISPR) machinery. We illustrate different strategies for the optimization of CDV cargo loading and retargeting, highlighting the versatility and tunability of these vehicles. Nonetheless, the lack of robust and standardized protocols for CDV production, purification, and quality assessment still hinders their widespread adoption to further CRISPR-based therapies as advanced "living drugs." We believe that a collective, multifaceted effort is urgently needed to address these critical issues and unlock the full potential of genome-editing technologies to yield safe, easy-to-manufacture, and pharmacologically well-defined therapies. Finally, we discuss the current clinical landscape of lung-directed gene therapies for cystic fibrosis and explore how CDVs could drive significant breakthroughs in in vivo gene editing for this disease.

The design and construction of synthetic therapeutic protocells capable of engaging in high-order assembly with living cells represent a significant challenge in synthetic biology and bioengineering. Inspired by cell membrane receptor-ligand systems, a protocell bioreactor is developed for targeted cancer cell elimination. This is achieved by constructing orthogonal, polysaccharide-based protocells (polysaccharidosomes, P-somes) through a bottom-up approach that leverages host-guest chemistry. The protocells are assembled via electrostatically-driven self-assembly of β-cyclodextrin (β-CD)-modified amino-dextran on a sacrificial template encapsulating glucose oxidase (GOx). To enable specific cancer cell targeting and catalytic activity, cell-targeting ligands (arginylglycylaspartic acid, cRGD) and catalase-like platinum-gold nanoparticles (Pt-AuNPs) are introduced through host-guest interactions, forming a fully functional, cell-targeting, bio-catalytic killer protocell. These protocells are programmed to spatially couple the GOx/Pt-AuNP catalytic reaction cascade. In the presence of glucose and hydroxyurea, this cascade generates a localized flux of nitric oxide (NO), which is exploited for in vitro cancer cell inhibition. Overall, the results highlight the potential of integrating orthogonal and synergistic tumor inhibition mechanisms within synthetic microcompartments. This platform demonstrates promise for future therapeutic applications, especially in cancer treatment, and represents a step forward in the development of programmable protocell-based therapeutic systems.

Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of secondary osteoporosis. Recently, the "bone-gut axis" theory has linked bone development with gut microbial diversity, community composition, and metabolites. Curcumin, a well-studied polyphenol, shows potential in mitigating bone loss and osteoporosis. Alendronate, a standard therapeutic agent for osteoporosis, serves as a positive control in this investigation. The study demonstrates the potency of curcumin in reducing bone loss and restoring bone mineral density, enhancing trabecular parameters notably through increased trabecular number, volume, and thickness and reduced bone marrow cavity size. Gut microbiome sequencing revealed that both curcumin and alendronate treatments similarly enhanced gut microbial diversity and altered microbiota composition, increasing beneficial bacteria (Akkermansia_muciniphila, Dubosiella_sp910585105, and Ruminococcus_sp910584195) while reducing harmful bacteria (Treponema_D_sp910584475 and Duncaniella_sp910584825). Furthermore, significant changes in serum levels of metabolites including raffinose, ursolic acid, spermidine, inosine, hypoxanthine, thiamine, and pantothenic acid were observed post-treatment with curcumin or alendronate. Importantly, these beneficial metabolites and microorganisms were negatively correlated with inflammatory cytokines. In conclusion, curcumin holds promise for use against GIOP by modulating the gut microbiome and serum metabolome as well as reducing systemic inflammation.

Exosomes from different sources have been used for therapeutic purposes to target stroke and other disorders. However, exosomes from endothelial progenitor cells (EPCs) have not been tested in any stroke model, and in vivo bio-distribution study is lacking. Targeted delivery of IV-administered exosomes has been a significant challenge. Delivery of exosomes to the brain is a daunting task, and a blood-brain barrier (BBB)-penetrable peptide is being considered. However, the next step in practical treatment will be delivering naïve (unmodified) exosomes to the stroke site without destroying host tissues or disrupting BBB, or the membranes of the delivery vehicles. Low-intensity-pulsed focused ultrasound (LIPFUS) is approved for clinical use in the musculoskeletal, transcranial brain, and physiotherapy clinics. The objectives of the proposed studies were to determine whether LIPFUS-mediated increased delivery of EPC-derived exosomes enhances stroke recovery and functional improvement in mice with transient middle cerebral artery occlusion (tMCAo) stroke.

To enhance exosome delivery to the stroke area, we utilized LIPFUS. We evaluated stroke volume using MRI at different time points and conducted behavioral studies parallel to MRI to determine recovery. Ultimately, we studied brain tissue using immunohistochemistry to assess the extent of stroke and tissue regeneration.

In vivo, imaging showed a higher accumulation of EPC exosomes following LIPFUS without any damage to the underlying brain tissues, increased leakage of albumin, or accumulation of CD45+ cells. Groups of mice (14-16 months old) were treated with Vehicle (PBS), LIPFUS only, EPC-exosomes only, and LIPFUS+EPC-exosomes. LIPFUS + EPC exosomes groups showed a significantly decreased stroke volume on day 7, decreased FluoroJade+ cells, and significantly higher numbers of neovascularization in and around the stroke areas compared to that of other groups.

Extracellular vesicles (EVs) have been explored as promising vehicles for drug delivery. One of the most valuable features of EVs is their ability to cross physiological barriers, particularly the blood-brain barrier (BBB). This significantly enhances the development of EV-based drug delivery systems for the treatment of CNS disorders. The present review focuses on the factors and techniques that contribute to the successful delivery of EV-based therapeutics to the brain. Here, we discuss the major methods of brain targeting which includes the utilization of different administration routes, capitalizing on the biological origins of EVs, and the modification of EVs through the addition of specific ligands on to the surface of EVs. Finally, we discuss the current challenges in large-scale EV production and drug loading while highlighting future perspectives regarding the application of EV-based therapeutics for brain delivery.

The development of targeted drugs for diseases of the central nervous system (CNS) is a significant challenge due to the structural complexity and functional specificities of these systems. Recently, exosomes have emerged as a promising therapeutic platform, given their unique capacity to traverse the blood-brain barrier and deliver bioactive molecules to target cells. This review examines recent advances in exosome research with a particular focus on CNS diseases, emphasizing their role as carriers of therapeutic cargo, including proteins, RNAs, and lipids. Nevertheless, significant challenges remain before exosome-based therapies can be translated from preclinical research to clinical applications. These include the need for scalable production and standardized isolation methods. Despite these hurdles, ongoing studies continue to shed light on the mechanisms of exosome-mediated neuroprotection and neurodegeneration. This paves the way for innovative therapeutic strategies to address CNS disorders.

Curcumin has a clear immunopharmacological effect and plays an important role as an immune agent in various immune diseases and tumor immunotherapy. To comprehensively and scientifically clarify and reflect the development process, current status, and research trends of curcumin in the field of immune regulation, and to provide reliable insights for discipline development strategies and future research expansion, this study systematically analyzes 3939 valid articles related to curcumin and immunity published between 2004 and 2024 from the Web of Science database. Using Citespace and R-bibliometrix software for bibliometric analysis, we create visual knowledge maps from multiple dimensions including overall publication output, influential research entities, highly cited papers, research topics and hotspots. The results indicate that the overall number of publications and citations is currently in a rapid development phase. China occupies a core position in this research field but has low collaboration intensity. The Egyptian Knowledge Bank (EKB) is the institution with the highest publication volume. Moreover, cluster analysis reveals that research hotspots are gradually shifting from fundamental pathology to topics involving broad social and environmental influences. The top five keywords with the most explosive citations-curcumin, inflammation, apoptosis, oxidative stress, and cancer-represent the most focused and influential research topics. Currently, curcumin immunology has developed a diversified research perspective, accumulating significant research in the areas of active substance basis, pharmacological activity, anti-inflammatory, and anti-cancer studies. The thematic evolution trends and keywords related to curcumin's immunological mechanisms summarized in this article provide insights and guidance for future research directions.

Traumatic brain injury (TBI) is a leading cause of disability in adults, significantly affecting patients' quality of life. Extracellular vesicles (EVs) derived from human adipose-derived mesenchymal stem cells (hADSCs) have demonstrated therapeutic potential in TBI treatment. However, their limited targeting ability, short half-life, and low bioavailability present significant challenges for clinical application. In this study, we engineered extracellular vesicles (EEVs) by transfecting hADSCs with lentivirus and incorporating ultra-small paramagnetic nanoparticles (USPNs), resulting in EVs with enhanced miRNA expression and targeted delivery capabilities. These EEVs were administered intranasally to specifically target injury sites, effectively modulating the NF-κB signaling pathway to suppress neuroinflammation. In both in vitro and in vivo assessments, EEVs exhibited superior efficacy in promoting neurofunctional recovery and neurogenesis after brain injury compared to unmodified EVs. Furthermore, validation using human brain organoid models confirmed EEVs' remarkable ability to suppress neuroinflammation, offering a promising strategy for TBI treatment.

Enveloped nanoparticles such as extracellular vesicles (EVs) and virus-like particles (VLPs) have emerged as promising nanocarriers capable of transporting bioactive molecules for drug delivery and vaccination. Optimized functionalization methodologies are required to increase the functionalization levels of these nanoparticles, enhancing their performance. Here, a bioorthogonal copper-free strain-promoted azide-alkyne cycloaddition (SPAAC) reaction has been optimized to functionalize human immunodeficiency virus type 1 (HIV-1) Gag-based VLPs and EVs. The optimization process has been carried out through reaction kinetics and design of experiments (DoE) using Cy5 as a reporter molecule. The functionalization of both VLPs and EVs has been studied using super-resolution fluorescence microscopy (SRFM), revealing remarkable differences between Gag-VLPs and coproduced EVs. EVs produced by mock transfection and cell growth have been functionalized achieving a mean of 3618.63 ± 48.91 and 6498.75 ± 352.71 Cy5 molecules covalently linked per particle (Cy5cov/particle), respectively. Different nanoparticles have been functionalized with two linear B-cell epitopes from the Spike protein of SARS-CoV-2, S315-338 TSNFRVQPTESIVRFPNITNLCPF and S648-663 GCLIGAEHVNNSYECD, and analyzed by an immunoassay with sera from COVID-19 patients. The obtained results validate the selected B-cell epitopes and highlight the potential of the optimized functionalization approach for the development of nanoparticle-based vaccines.

Traditional drug therapies suffer from problems such as easy drug degradation, side effects, and treatment resistance. Traditional disease diagnosis also suffers from high error rates and late diagnosis. Extracellular vesicles (EVs) are nanoscale spherical lipid bilayer vesicles secreted by cells that carry various biologically active components and are integral to intercellular communication. EVs can be found in different body fluids and may reflect the state of the parental cells, making them ideal noninvasive biomarkers for disease-specific diagnosis. The multifaceted characteristics of EVs render them optimal candidates for drug delivery vehicles, with evidence suggesting their efficacy in the treatment of various ailments. However, poor stability and easy degradation of natural EVs have affected their applications. To solve the problems of poor stability and easy degradation of natural EVs, they can be engineered and modified to obtain more stable and multifunctional EVs. In this study, we review the shortcomings of traditional drug delivery methods and describe how to modify EVs to form engineered EVs to improve their utilization. An innovative stimulus-responsive drug delivery system for EVs has also been proposed. We also summarize the current applications and research status of EVs in the diagnosis and treatment of different systemic diseases, and look forward to future research directions, providing research ideas for scholars.

Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.

Extracellular vesicles (EVs) participate in intercellular communication and play an essential role in physiological and pathological processes. In recent years, EVs have garnered significant attention as cell-free therapeutic alternatives, vectors for drug and gene delivery, biomarkers for disease diagnosis and prognosis, vaccine development, and nutraceuticals. The biodistribution of EVs critically influences their efficacy and toxicity. Therefore, this review aims to discuss the main factors influencing the biodistribution of unmodified EVs, highlighting their distribution patterns, advantages, limitations, and applications under different routes of administration. In addition, we provide a comprehensive discussion of the currently available sources of EVs and summarize the current status of the therapeutic potentials of EVs. By optimizing administration routes and selecting appropriate EV sources, we aim to offer valuable insights to enhance the delivery efficiency and therapeutic efficacy of EVs to target tissues.

Exosomes, which are nano-sized natural vesicles secreted by cells, are crucial for intercellular communication and interactions, playing a significant role in various physiological and pathological processes. Their characteristics, such as low toxicity and immunogenicity, high biocompatibility, and remarkable drug delivery capabilities-particularly their capacity to traverse the blood-brain barrier-make exosomes highly promising vehicles for drug administration in the treatment of brain disorders. This review provides a comprehensive overview of exosome biogenesis and isolation techniques, strategies for the drug loading and functionalization of exosomes, and exosome-mediated blood-brain barrier penetration mechanisms, with a particular emphasis on recent advances in exosome-based drug delivery for brain disorders. Finally, we address the opportunities and challenges associated with utilizing exosomes as a drug delivery system for the brain, summarizing the barriers to clinical translation and proposing future research directions.

The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored. Compared with conventional treatments, small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing. As a result of recent technological advances, efficient small nucleic acid delivery for therapeutic and biomedical applications has been achieved, accelerating their clinical translation. Here, we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms. We also discuss the key advances in the design, development and therapeutic application of each delivery platform. Furthermore, this review presents comprehensive profiles of currently approved small nucleic acid drugs, including 11 antisense oligonucleotides (ASOs), 2 aptamers and 6 siRNA drugs, summarizing their modifications, disease-specific mechanisms of action and delivery strategies. Other candidates whose clinical trial status has been recorded and updated are also discussed. We also consider strategic issues such as important safety considerations, novel vectors and hurdles for translating academic breakthroughs to the clinic. Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously "undruggable" targets, suggesting that they could be useful for guiding the development of additional clinical candidates.

High-dose methotrexate (HD-MTX) serves as the cornerstone of central nervous system lymphoma (CNSL) treatment, but its efficacy is limited due to low blood-brain barrier (BBB) penetration and adverse effects. This study is focused on an exosome-based drug delivery approach aimed at enhancing BBB permeability, thereby reducing the required dosage of methotrexate (MTX) while ensuring specific targeting of CNSL.

Human adipose-derived mesenchymal stem cells (hAMSCs) were modified with a lentiviral vector encoding anti-CD19, incorporated into exosomes characterized by colloidal gold immunoelectron microscopy and Nano flow cytometry. MTX loaded into anti-CD19-Exos via co-incubation, assessed for loading and encapsulation efficiencies using HPLC. In vitro BBB model constructed using hCMEC/D3 and astrocytes to investigate BBB permeability. In vivo efficacy of anti-CD19-Exo-MTX evaluated in intracranial CNSL models using MRI. Biodistribution tracked with DiR-labeled exosomes, drug concentration in CSF measured by HPLC. LC-MS/MS identified and characterized exosomal proteins analyzed using GO Analysis. Neuroprotective effects of exosomal proteins assessed with TUNEL and Nissl staining on hippocampal neurons in CNSL models. Liver and kidney pathology, blood biochemical markers, and complete blood count evaluated exosomal protein effects on organ protection and MTX-induced myelosuppression.

We generated anti-CD19-Exo derived from hAMSCs. These adapted exosomes effectively encapsulated MTX, enhancing drug accessibility within lymphoma cells and sustained intracellular accumulation over an extended period. Notably, anti-CD19-Exo-MTX interacted with cerebrovascular endothelial cells and astrocytes of the BBB, leading to endocytosis and facilitating the transportation of MTX across the barrier. Anti-CD19-Exo-MTX outperformed free MTX in vitro, exhibiting a more potent lymphoma-suppressive effect (P < 0.05). In intracranial orthotopic CNSL models, anti-CD19-Exo-MTX exhibited a significantly reduced disease burden compared to both the MTX and Exo-MTX groups, along with prolonged overall survival (P < 0.05). CSF drug concentration analysis demonstrated enhanced stability and longer-lasting drug levels for anti-CD19-Exo-MTX. Anti-CD19-Exo-MTX exhibited precise CNSL targeting with no organ toxicity. Notably, our study highlighted the functional potential of reversal effect of hAMSCs-exosomes on MTX-induced neurotoxicity, hepatic and renal impairment, and myelosuppression.

We present anti-CD19-Exo-MTX as a promising exosome-based drug delivery platform that enhances BBB permeability and offers specific targeting for effective CNSL treatment with reduced adverse effects.

Current treatments for acute myeloid leukemia (AML) remain challenging and are characterized by poor clinical outcomes. Exosomes, cell-derived membranous vesicles, have been emerging as a new modality of therapy. Here, we designed and generated genetically reprogrammed exosomes with surface-displayed antibodies and immunoregulatory proteins, namely programmed immune-engaging exosomes (PRIME Exos). By simultaneously targeting T cells and AML cells expressing C-type lectin-like molecule-1 (CLL-1), PRIME Exos can elicit tumor-specific immune responses and sustain cellular immunity against AML by modulating programmed death 1 (PD-1)- and CD27-mediated immune checkpoint pathways. In preclinical models of AML, PRIME Exos have shown promising efficacy and safety for suppressing leukemia expansion. This study developed a new exosome-based approach for AML immunotherapy.

Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease among the aged population. The primary objective of this study was to assess the therapeutic potential of puerarin loaded bone marrow mesenchymal stem cell-derived exosomes (Pue@BMSC-Exo), and reveal their inflammatory regulating mechanisms through affecting the nuclear factor kappa-B (NF-κB) signaling pathway. In this study, exosomes derived from BMSCs were isolated and identified. Cell proliferation and migration were evaluated by CCK-8 and scratch methods. Furthermore, histological and micro-computed tomography analysis were performed to assess alterations of articular cartilage in OA rats. Results showed that BMSC-Exo and Pue@BMSC-Exo conformed with the basic characteristics of exosomes. BMSC-Exo increased the solubility of Pue and enhanced drug uptake by chondrocytes. In addition, Pue@BMSC-Exo stimulated proliferation and migration of chondrocyte, and also promoted cartilage repair by reducing matrix metalloproteinase MMP13 production and increasing type II collagen (Col2) synthesis. Furthermore, Pue@BMSC-Exo, by effectively inhibiting the NF-κB signaling pathway, reduced the production of inflammatory mediators and attenuated the release of the inflammatory marker nitric oxide (NO), ultimately ameliorating the damage of chondrocyte. These findings exhibited the potential therapeutic significance of Pue@BMSC-Exo in OA and warranted further exploration in clinical applications.