本周hzangs在最新文献中选取了10篇分享给大家，第1篇文章是刘光慧教授团队发表的关于MSC来源囊泡可以抗衰老的报道；第2篇文章介绍了焦亡囊泡作为个性化疫苗的可行性；第3篇文章介绍了一种单囊泡成像技术；第6篇文章是方法学的报道，对比了从器官中分离囊泡的不同策略的优缺点。
- Senescence-resistant human mesenchymal progenitor cells counter aging in primates.
抗衰老的人类间充质祖细胞可抵抗灵长类动物的衰老。
[Cell] PMID: 40516525
Abstract: Aging is characterized by a deterioration of stem cell function, but the feasibility of replenishing these cells to counteract aging remains poorly defined. Our study addresses this gap by developing senescence (seno)-resistant human mesenchymal progenitor cells (SRCs), genetically fortified to enhance cellular resilience. In a 44-week trial, we intravenously delivered SRCs to aged macaques, noting a systemic reduction in aging indicators, such as cellular senescence, chronic inflammation, and tissue degeneration, without any detected adverse effects. Notably, SRC treatment enhanced brain architecture and cognitive function and alleviated the reproductive system decline. The restorative effects of SRCs are partly attributed to their exosomes, which combat cellular senescence. This study provides initial evidence that genetically modified human mesenchymal progenitors can slow primate aging, highlighting the therapeutic potential of regenerative approaches in combating age-related health decline.
- Engineering pyroptotic vesicles as personalized cancer vaccines.
设计焦亡囊泡作为个性化癌症疫苗。
[Nat Nanotechnol] PMID: 40379868
Abstract: Tumour vaccines are designed to stimulate the host's immune system against existing tumours or tumour recurrence. However, individual differences, tumour heterogeneity and side effects hinder the applications of current tumour vaccines and require the development of personalized cancer vaccines. To overcome these challenges, we engineered pyroptotic vesicles-extracellular vesicles formed during tumour cell pyroptosis-as a tumour vaccine platform. The extracted pyroptotic vesicles possess abundant tumour antigens and potent immune-stimulating ability and, loaded into a biocompatible hydrogel, they can be implanted into post-surgical tumour cavities to prevent tumour recurrence. The pyroptotic-vesicle-based vaccine outperforms both exosome- and apoptotic-body-based vaccines in inhibiting tumour recurrence and metastasis in different post-surgical mouse models. Mechanistic studies reveal that the pyroptotic-vesicle-based vaccine could stimulate robust antigen-specific dendritic cell and T cell immune responses against both artificial OVA antigens and cancer neoantigens. In sum, our vaccine platform can be tailored to stimulate robust antitumour immune responses for treating individual cancer patients.
- Single extracellular vesicle imaging via rolling circle amplification-expansion microscopy.
通过滚环扩增-扩展显微镜进行单个细胞外囊泡成像。
[Nat Commun] PMID: 40804235
Abstract: Extracellular vesicles (EVs) from biological fluids can provide critical information for minimally invasive diagnostics and treatment monitoring, but their nanoscale size, low biomarker abundance, and heterogeneity pose challenges. Here, we integrate rolling circle amplification with expansion microscopy (RCA-ExM) to achieve super-resolution multi-omics profiling of single EVs using conventional fluorescence microscopy. Sensitive multimodal biomarker detection is achieved by employing RCA to detect switch hairpin probe-labeled EV membrane proteins, and EV-liposome fusion to detect EV miRNAs via delivery of specific molecular beacons and a signal-amplifying enzyme circuit. Next, hydrogel-mediated expansion is employed to enlarge the fused EVs to permit single-EV detections. RCA-ExM quantitation of miRNA-21 levels in EpCAM+PD-L1+ plasma EVs from a clinical cohort (n = 86) successfully distinguishes cancer patients from healthy donors and differentiates 3 categories of immunotherapy efficacy. RCA-ExM therefore exhibits significant promise for more sensitive and specific diagnostics, and treatment monitoring applications.
- Extracellular vesicle-based drug overview: research landscape, quality control and nonclinical evaluation strategies.
基于细胞外囊泡的药物概述：研究前景、质量控制和非临床评估策略。
[Signal Transduct Target Ther] PMID: 40804047
Abstract: Extracellular vesicles share lipid‒protein membranes with their parent cells, allowing for the targeted transfer of bioactive cargo to recipient cells for functional modulation. The biological features allow extracellular vesicles to serve both as intrinsic therapeutics and as engineered delivery vehicles for targeted molecule transport. In recent years, extracellular vesicle-based therapy has shown great potential as a new therapeutic approach for traumatic conditions and degenerative, acute, and refractory diseases. As extracellular vesicle engineering continues to evolve, more innovative drugs are expected to receive investigational new drug approvals and marketing approvals from regulatory agencies in the future. However, many challenges exist in terms of mechanistic understanding, engineering modifications, manufacturing processes, quality control, and nonclinical research, and no drug regulatory authorities have currently issued specific technical evaluation guidelines for extracellular vesicle-based drugs, all of which have hindered the clinical translation of these drugs. In this article, which is focused primarily on extracellular vesicles derived from mammalian cells, we summarize the clinical translation and process development research status of extracellular vesicle-based drugs and propose both general considerations and key aspects of quality control strategies and nonclinical evaluations in the development process. The aim of this review is to provide valuable references for the development and evaluation of extracellular vesicle-based products, accelerate the clinical translation process, and benefit patients as soon as possible.
- Tumour-derived microparticles obtained through microwave irradiation induce immunogenic cell death in lung adenocarcinoma.
通过微波辐射获得的肿瘤衍生微粒可诱导肺腺癌的免疫原性细胞死亡。
[Nat Nanotechnol] PMID: 40389640
Abstract: Tumour-derived microparticles (TMPs), extracellular vesicles traditionally obtained upon ultraviolet (UV) radiation of tumour cells, hold promise in tumour immunotherapies and vaccines and have demonstrated potential as drug delivery systems for tumour treatment. However, concerns remain regarding the limited efficacy and safety of UV-derived TMPs. Here we introduce a microwave (MW)-assisted method for preparing TMPs, termed MW-TMPs. Brief exposure of tumour cells to short-wavelength MW radiation promotes the release of TMPs showing superior in vivo antitumour activity and safety compared with UV-TMPs. MW-TMPs induce immunogenic cell death and reprogramme suppressive tumour immune microenvironments in different lung tumour models, enabling dual targeting of tumour cells by natural killer and T cells. We show that they can efficiently deliver methotrexate to tumours, synergistically boosting the efficacy of PD-L1 blockade. This MW-TMP development strategy is simpler, more efficient and safer than traditional UV-TMP methods.
- Comparative Assessment of Whole Organ Tissue Processing Methods for the Isolation of Extracellular Vesicles From Intact Organs.
从完整器官中分离细胞外囊泡的全器官组织处理方法的比较评估。
[J Extracell Vesicles] PMID: 40903824
Abstract: Extracellular vesicles (EVs) are small anuclear cellular membrane encapsulated fragments of importance for cellular interaction and transfer of information. These small vesicles, diverse in size and functionality, can be obtained from cells, tissues and bodily fluids. A complicated step for obtaining EVs from whole organs is understanding the optimal methodology for organ processing. In this study, we have examined two different techniques: one enzymatic and one novel non-enzymatic automated tissue dissociation (ATD) machine. Animals were perfused, organs extracted, and techniques comparatively applied. We have used these techniques for organ-based dissociation followed by EV isolation from the dissociated tissues (heart, kidney, lung). While both approaches allow isolation of intact EVs there are distinct differences in overall cell and particle yields. Our study highlights tissue specific inter-organ variability and differential impact of dissociation strategies on organ-based EV profiles, as well as cellular characteristics. Our findings indicate that EV yields and characteristics varies between enzymatic and ATD techniques as well as between organs with highest EV yield obtained from kidneys following enzymatic dissociation. Our findings can be rapidly transferred to other setups or developed to enable enumeration and characterization of EVs obtained from whole organs in physiological and pathological settings.
- Defective neutrophil-derived exosomes facilitate macrophage activation through miR-122-5p in Behçet's disease.
在白塞氏病中，缺陷型中性粒细胞衍生的外泌体通过miR-122-5p 促进巨噬细胞活化。
[Nat Commun] PMID: 40897707
Abstract: Behçet's disease (BD) is a life-threatening systemic vasculitis characterized by polymorphonuclear neutrophils (PMN) and macrophage activation. However, the interaction of PMN and macrophages remains elusive. To elucidate the potential dysregulation of BD PMN exosomes on macrophage activation, PMN exosomes from both BD patients and healthy controls are isolated, quantified and incubated with macrophages. We find that BD PMN exosomes are decreased and negatively correlated with C-reactive protein (CRP). PMN exosomes can suppress IL-6, TNF, CD80 and CD86 expressions on macrophages, which are attenuated in BD PMN exosomes. In addition, by miRNA sequencing of PMN exosomes, RNA sequencing of miRNA-transfected macrophages, and dual luciferase reporter assay validation of the miRNA target, we find that miR-122-5p is decreased in BD PMN exosomes, targeting IRF5, suppressing TLR4 signaling and IFN-β autocrine, eventually downregulating macrophage activation. Our study illustrates that BD PMN exosomes are decreased in both quantity and miR-122-5p, which impairs the potential immunoregulatory effects on macrophages through degrading IRF5 and suppressing IFN-β autocrine, shedding light on the interaction mechanism between PMN and macrophages.
- Circulatory extracellular vesicles transport complement C1q for promoting neuronal amyloid-βproduction in Alzheimer's disease.
循环细胞外囊泡运输补体 C1q 以促进阿尔茨海默病中的神经元淀粉样蛋白-β 的产生。
[J Neuroinflammation] PMID: 40883774
Abstract: Alzheimer’s disease (AD) is the most common type of dementia. A major pathological feature of AD is the aggregation of amyloid-β (Aβ), primarily driven by β-secretase (BACE1) activity. However, the mechanisms underlying continuous Aβ accumulation remain unclear. Circulating extracellular vesicles (EVs) may play a crucial role in AD progression. Here, we investigate whether circulating EVs in AD promote Aβ generation and aggregation. In this study, we found that compared to WTEVs (circulating EVs isolated from WT mice), APPEVs (circulating EVs isolated from APP/PS1 mice) showed higher concentrations and activated the JAK2-STAT1 pathway in neurons, upregulating BACE1 expression and activity. This cascade promoted amyloid precursor protein (APP) β-cleavage in lipid rafts, inducing substantial Aβ generation. Proteomic analysis revealed complement C1q in APPEVs as a key protein activating the JAK2-STAT1-BACE1 pathway. Furthermore, in vivo experiments demonstrated that intravenously injected APPEVs crossed the blood-brain barrier without damaged the epithelial tight junction, promoting BACE1 expression in neurons, and enhancing Aβ production and aggregation in brain. Inhibition of C1q mitigated these effects in both in vitro and in vivo experiments. In conclusion, during the progression of AD, circulating EVs containing complement C1q are delivered to neurons, activating their JAK2-STAT1 signaling pathway. This activation upregulates the expression of BACE1, subsequently enhancing the β-cleavage of APP in lipid rafts. These events lead to a substantial increase in Aβ production, exacerbating the pathological progression of AD.
- Exosome-mediated microglia-astrocyte interactions drive neuroinflammation in Parkinson's disease with Peli1 as a potential therapeutic target.
外泌体介导的小胶质细胞-星形胶质细胞相互作用导致帕金森病的神经炎症，而 Peli1 是潜在的治疗靶点。
[Pharmacol Res] PMID: 40816423
Abstract: Neuroinflammation is a key feature of Parkinson's disease (PD), characterized by activated microglia and the conversion of astrocytes into the neurotoxic phenotype, exacerbating the neuroinflammation. In PD, microglia critically drive neurotoxic reactive astrocytes (A1, A1-like, or neuroinflammatory reactive astrocytes)-though the underlying mechanisms remain elusive. Given the established role of exosomes as critical intercellular messengers, we investigated whether microglia-derived exosomes contribute to neurotoxic astrocyte transformation. Our findings demonstrate that microglial depletion via PLX3397 significantly attenuated α-synuclein pre-formed fibrils (α-syn PFF)-induced neurotoxic reactive astrocytes. Crucially, purified microglial exosomes alone proved sufficient to drive astrocyte polarization toward the neurotoxic phenotype in mice. Complementary approaches-exosome depletion from microglial supernatants and GW4869-mediated exosome secretion blockade-convergently alleviated neurotoxic astrocytic phenotype conversion, verifying exosome-dependent mechanisms. Mechanistically, PFF-activated microglial exosomes carried proinflammatory factors and toxic α-syn oligomers. These cargo components exacerbated neuroinflammation through induction of the neurotoxic astrocyte phenotype and direct mediation of neuronal damage. Critically, upon intrastriatal injection, these exosomes were internalized by astrocytes in the striatum and substantia nigra, triggering concurrent astrocyte proliferation and neurotoxic phenotypic conversion. Additionally, we identify Peli1, an E3 ubiquitin ligase selectively enriched in microglia, as a key regulator of microglia activation and exosome release. Peli1 inhibition alleviates microglia activation and neurotoxic astrocyte conversion. Moreover, our findings reveal a feedback loop between neurotoxic astrocytes and microglia, wherein neurotoxic astrocytes upregulate Peli1 expression in microglia, further promoting neuroinflammation. This study highlights microglial exosomes in regulating neurotoxic astrocyte activation and identifies Peli1 as a novel target for PD intervention.
- Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation.
肥胖相关的巨噬细胞通过传播线粒体碎片来控制脂肪干细胞铁死亡和内脏脂肪功能障碍。
[Nat Commun] PMID: 40813577
Abstract: Morbid obesity induces adipose stem cell (ASC) shortage that impairs visceral adipose tissue (VAT) homeostasis. Macrophages cooperate with ASCs to regulate VAT metabolism, their impact on ASC shortage remains elusive. TNF-α-induced protein 8-like 2 (TIPE2) is an important regulator in immune cells, its expression in VAT macrophages and function in macrophage-ASC crosstalk are largely unknown. Here, TIPE2 loss in VAT macrophages promotes ASC ferroptosis to aggravate diet-induced obesity and metabolic disorders in male mice, which can be corrected by macrophage-specific TIPE2 restoration in VAT. Mechanistically, TIPE2-deficient macrophages propagate mitochondrial fragmentation and reduce delivery of exosomal ferritin toward ASCs, resulting in mitochondrial ROS and Fe2+overload that dictates ASC ferroptosis. TIPE2 interacts with IP3R to constrain IP3R-Ca2+-Drp1 axis, thereby preventing excessive mitochondrial fission and enabling macrophages to protect against ASC ferroptosis. This study reveals distinct obesity-associated macrophages that dictate ASC ferroptosis, and proposes macrophage TIPE2 as therapeutic target for obesity-related diseases.
今天的整理就到这里。希望大家可以有所收获。大家下周见！
