bims-engexo Biomed News
on Engineered exosomes
Issue of 2025–04–06
eight papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Engineered extracellular vesicles as imaging biomarkers and therapeutic applications for urological diseases.
  2. Endoscopic nasal delivery of engineered endothelial progenitor cell-derived exosomes improves angiogenesis and neurological deficits in rats with intracerebral hemorrhage.
  3. Engineered Extracellular Vesicles Derived from Juvenile Mice Enhance Mitochondrial Function in the Aging Bone Microenvironment and Achieve Rejuvenation.
  4. Engineered Extracellular Vesicles Loaded with MiR-100-5p Antagonist Selectively Target the Lesioned Region to Promote Recovery from Brain Damage.
  5. Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.
  6. RVG engineered extracellular vesicles-transmitted miR-137 improves autism by modulating glucose metabolism and neuroinflammation.
  7. Locoregional Immune Checkpoint Blockade and Remodeling of Lymph Nodes by Engineered Dendritic Cell-Derived Exosomes for Suppressing Tumor Progression and Metastasis.
  8. Arg-Gly-Asp engineered mesenchymal stem cells as targeted nanotherapeutics against kidney fibrosis by modulating m6A.
  1. Mater Today Bio. 2025 Jun;32 101646
    Engineered extracellular vesicles as imaging biomarkers and therapeutic applications for urological diseases.
    Liao-Yuan Li, Si-Yuan Liang, Mao-Ping Cai, Jian-Chao Ge, Hai-Song Tan, Cheng-Bang Wang, Bin Xu.
      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.
    Keywords:  Biomarker; Extracellular vesicles; Imaging; Therapy; Urological diseases
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101646
  2. Mater Today Bio. 2025 Jun;32 101652
    Endoscopic nasal delivery of engineered endothelial progenitor cell-derived exosomes improves angiogenesis and neurological deficits in rats with intracerebral hemorrhage.
    Gui Wan, Zhenwei Li, Lingui Gu, Ye Sun, Yuhe Wang, Yiqing Wang, Ruxu Geng, Yangyang Chen, Wenbin Ma, Xinjie Bao, Renzhi Wang.
      Intracerebral hemorrhage (ICH) remains a life-threatening condition due to its high mortality and limited treatment options. This study explores a novel therapeutic strategy using engineered exosomes derived from endothelial progenitor cells (EPC-EXOs) to improve ICH outcomes. EPC-EXOs were modified with a CD47-enriched red blood cell membrane via co-extrusion to enhance their anti-phagocytic properties, thereby reducing degradation by activated microglia after ICH. A minimally invasive endoscopic-guided delivery system was developed to facilitate the targeted intranasal administration of these engineered EPC-EXOs (m-Oe-EXOs), allowing direct entry into brain tissue. We confirmed m-Oe-EXOs' high retention and effective distribution in the brain. Functional analysis demonstrated that EPC-EXOs significantly promoted the proliferation, migration, and angiogenesis of brain microvascular endothelial cells (BMECs), with proteomic analysis identifying HSP90 as a key protein activating the Akt pathway in BMECs. In vivo, m-Oe-EXOs demonstrated therapeutic efficacy by improving blood-brain barrier integrity, reducing hematoma volume, and enhancing neurological recovery in ICH rats. Collectively, our findings highlight the potential of minimally invasive, endoscopic-guided delivery of m-Oe-EXOs as an innovative approach for ICH treatment, providing new insights into targeted, exosomes-based regenerative therapies.
    Keywords:  Blood-brain barrier; Brain microvascular endothelial cells; Endothelial progenitor cell exosomes; HSP90; Intracerebral hemorrhage; Nasal endoscopic delivery
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101652
  3. ACS Nano. 2025 Apr 04.
    Engineered Extracellular Vesicles Derived from Juvenile Mice Enhance Mitochondrial Function in the Aging Bone Microenvironment and Achieve Rejuvenation.
    Jiaqian Zheng, Yipeng Ren, Junhua Ke, Guanglin Zhu, Zhen Wang, Xuetao Shi, Yingjun Wang.
      Aging-related bone degeneration and impaired healing capacity remain significant challenges in regenerative medicine, necessitating innovative, efficient, and targeted strategies to restore bone health. Here, we engineered extracellular vesicles (EVs) derived from the serum of pretreated juvenile mice, with the goals of reversing aging, enhancing osteogenic potential, and increasing bioavailability to rejuvenate the aging bone environment. First, we established bone healing models representing different phases of healing to identify the EV type with the highest potential for improving the bone microenvironment in older individuals. Second, we employed DSS6 for bone targeting to enhance the biological effects of the selected EVs in vivo. The engineered EVs effectively targeted bone repair sites and promoted fracture healing more effectively than unmodified EVs in older mice. RNA sequencing revealed that the translocase of outer mitochondrial membrane 7 (Tomm7) is crucial for the underlying mechanism. Silencing Tomm7 significantly diminished the positive regulatory effects of the EVs. Specifically, the engineered EVs may enhance mitochondrial function in aging cells by activating the Tomm7-mediated Pink1/Parkin mitophagy pathway, promoting stemness recovery in aging bone marrow stromal cells (BMSCs) and reversing the adverse conditions of the aging bone microenvironment. Overall, the developed engineered EVs derived from serum from juvenile mice offer an alternative approach for treating aging bones. The identified underlying biological mechanisms provide a valuable reference for precision treatment of aging bones in the future.
    Keywords:  aging tissue rejuvenation; bone-targeting; extracellular vesicles; mitophagy; rejuvenation
    DOI:  https://doi.org/10.1021/acsnano.4c17989
  4. Neurosci Bull. 2025 Apr 01.
    Engineered Extracellular Vesicles Loaded with MiR-100-5p Antagonist Selectively Target the Lesioned Region to Promote Recovery from Brain Damage.
    Yahong Cheng, Chengcheng Gai, Yijing Zhao, Tingting Li, Yan Song, Qian Luo, Danqing Xin, Zige Jiang, Wenqiang Chen, Dexiang Liu, Zhen Wang.
      Hypoxic-ischemic (HI) brain damage poses a high risk of death or lifelong disability, yet effective treatments remain elusive. Here, we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice. Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery, through inhibiting the cleaved-caspase-3 level, microglia activation, and the release of proinflammation cytokines following HI injury. Engineered extracellular vesicles (EVs) containing neuron-targeting rabies virus glycoprotein (RVG) and miR-100-5p antagonists (RVG-EVs-Antagomir) selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery. Both pre- and post-HI administration showed therapeutic benefits. Mechanistically, we identified protein phosphatase 3 catalytic subunit alpha (Ppp3ca) as a novel candidate target gene of miR-100-5p, inhibiting c-Fos expression and neuronal apoptosis following HI insult. In conclusion, our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.
    Keywords:  Extracellular vesicles; MicroRNAs; Neonatal hypoxic-ischemic brain damage; Neuronal survival; Protein phosphatase 3 catalytic subunit alpha
    DOI:  https://doi.org/10.1007/s12264-025-01376-6
  5. J Extracell Vesicles. 2025 Apr;14(4): e70035
    Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.
    Xiabing Lyu, Tomoyoshi Yamano, Kanto Nagamori, Shota Imai, Toan Van Le, Dilireba Bolidong, Makie Ueda, Shota Warashina, Hidefumi Mukai, Seigo Hayashi, Kazutaka Matoba, Taito Nishino, Rikinari Hanayama.
      Extracellular vesicles (EVs) are important mediators of cell-cell communication, including immune regulation. Despite the recent development of several EV-based cancer immunotherapies, their clinical efficacy remains limited. Here, we created antigen-presenting EVs to express peptide-major histocompatibility complex (pMHC) class I, costimulatory molecule and IL-2. This enabled the selective delivery of multiple immune modulators to antigen-specific CD8+ T cells, promoting their expansion in vivo without severe adverse effects. Notably, antigen-presenting EVs accumulated in the tumour microenvironment, increasing IFN-γ+ CD8+ T cell and decreasing exhausted CD8+ T cell numbers, suggesting that antigen-presenting EVs transformed the 'cold' tumour microenvironment into a 'hot' one. Combination therapy with antigen-presenting EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumours. We successfully engineered humanized antigen-presenting EVs, which selectively stimulated tumour antigen-specific CD8+ T cells. In conclusion, engineering EVs to co-express multiple immunomodulators represents a promising method for cancer immunotherapy.
    Keywords:  antigen presentation; cancer immunotherapy; drug delivery; extracellular vesicle; targeted cytokine delivery
    DOI:  https://doi.org/10.1002/jev2.70035
  6. Mol Psychiatry. 2025 Apr 02.
    RVG engineered extracellular vesicles-transmitted miR-137 improves autism by modulating glucose metabolism and neuroinflammation.
    Qian Qin, Mengyue Li, Linlin Fan, Xin Zeng, Danyang Zheng, Han Wang, Yutong Jiang, Xinrui Ma, Lei Xing, Lijie Wu, Shuang Liang.
      Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder. The microglia activation is a hallmark of ASD, which involves increased glycolysis. Elevated glycolysis regardless of oxygen availability, known as "Warburg effect", is crucial to pathogenesis in neuropsychiatric disorders. Psychiatric risk gene MIR137 plays an important role in neurogenesis and neuronal maturation, but the impact on neuroinflammation and glucose metabolism remains obscure. Extracellular vesicles (EVs) can delivery miR-137 crossing the blood-brain barrier. Meanwhile, EVs can help miR-137 avoid being rapidly degraded by endogenous nucleases. Here, after first detecting miR-137 decreased both in the peripheral blood of individuals with ASD and the serum and cerebellum of BTBR mice, we demonstrated that microglia activation, the level of lactate and key enzymes (HK2, PKM2 and LDHA) involved in glycolysis were increased significantly in BTBR mice. Of particular note, EVs engineered by rabies virus glycoprotein (RVG) could promote the miR-137 (RVG-miR137-EVs) targeted to the brain accurately, and alleviated autism-like behaviors. Pro-inflammatory activation of BTBR mice was considerably inhibited by RVG-miR137-EVs via tail vein administration, accompanied by decreased lactate production. Mechanically, these effects were attributed to TLR4, the key target gene, which was regulated by miR-137. The TLR4/NF-κB pathway was inhibited, subsequently reducing HIF-1α and repressing the transcription of HK2, PKM2 and LDHA involved in glycolysis. Pharmacological inhibition of glycolysis and TLR4 attenuated microglial activation and lactate production, ultimately improved autism-like behaviors of BTBR mice. In conclusion, our results indicated that miR-137 could alleviate autism-like behaviors by HIF-1α-mediated adaptive metabolic changes in glycolysis and neuroinflammation.
    DOI:  https://doi.org/10.1038/s41380-025-02988-0
  7. Adv Sci (Weinh). 2025 Apr 03. e2500139
    Locoregional Immune Checkpoint Blockade and Remodeling of Lymph Nodes by Engineered Dendritic Cell-Derived Exosomes for Suppressing Tumor Progression and Metastasis.
    Yizhen Wang, Xiaomin Guo, Jingya Qin, Yifan Xue, Peng Zhang, Yadong Liu, Moyang Chen, Guanghao Zhu, Xinqiu Song, Lili Cheng, Bo Liu, Jie Liu, Jie Ren.
      Tumor-draining lymph nodes (TDLNs) are the primary sites of eliciting anti-tumor immunity, which play an important role in controlling tumor progression and metastasis. However, the immunosuppressive microenvironment of TDLNs propels the formation of pre-metastatic niche, in which the immunocytes are dysfunctional, and the high expression of programmed death-ligand 1 (PD-L1) on dendritic cells (DCs) restricts the activation of cytotoxic T lymphocytes. Herein, engineered exosomes (EmDEX@GA) are developed for locoregional immunomodulation of TDLNs. EmDEX@GA possess CC-chemokine receptor 7 (CCR7) -dependent LN homing capacity and over-expressed programmed cell death protein 1 (PD-1) for immune checkpoint blockade (ICB). The loaded stimulator of interferon genes (STING) agonist can reinforce anti-tumor immunity through STING pathway activation. In orthotopic breast cancer mouse model, local administration of EmDEX@GA remodels the immunosuppressive microenvironment of TDLNs and elicits potent anti-tumor immunity, resulting in the suppression of tumor as well as the reduction of lymph node metastasis and distant metastasis. Compared with systemic ICB, local immunotherapy with EmDEX@GA has better therapeutic efficacy on suppressing distant metastasis. Moreover, the study suggests that the occurrences of distant metastasis are associated with the immunosuppressive microenvironment rather than the metastasis in TDLNs, indicating that targeted immunomodulation of TDLNs is necessary.
    Keywords:  engineered exosomes; immune microenvironment; local immunotherapy; metastasis; tumor‐draining lymph nodes
    DOI:  https://doi.org/10.1002/advs.202500139
  8. Acta Biomater. 2025 Mar 28. pii: S1742-7061(25)00217-X. [Epub ahead of print]
    Arg-Gly-Asp engineered mesenchymal stem cells as targeted nanotherapeutics against kidney fibrosis by modulating m6A.
    Xin Zhang, Jiaqi Zhao, Rui Ge, Xiangyu Zhang, Haihan Sun, Yuhan Guo, Yanping Wang, Lu Chen, Shulin Li, Jing Yang, Dong Sun.
      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.
    Keywords:  EV; RGD peptide; SIRT1; m6A; renal interstitial fibrosis
    DOI:  https://doi.org/10.1016/j.actbio.2025.03.042
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