bims-engexo Biomed News
on Engineered exosomes
Issue of 2025–05–04
six papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Multi-Omics Analysis of the Immune Effect of the Engineered Exosome Drug Delivery System in Inducing Macrophage Apoptosis.
  2. An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity.
  3. Exosomes in Systemic Autoimmune Diseases: Recent Advances in Diagnostic Biomarkers and Therapeutic Applications.
  4. Engineered exosomes improve the effects of curcumin on protecting mitochondria of neurons in Alzheimer's disease.
  5. Exosome-Modified AAV Gene Therapy Attenuates Autoimmune Hepatitis via Enhanced Regulatory T Cell Targeting and Immune Modulation.
  6. Human Mesenchymal Stem Cell-Derived Exosomes as Engineering Vehicles of Daunorubicin for Targeted c-Mpl+ AML Therapy.
  1. Pharmaceutics. 2025 Apr 08. pii: 494. [Epub ahead of print]17(4):
    Multi-Omics Analysis of the Immune Effect of the Engineered Exosome Drug Delivery System in Inducing Macrophage Apoptosis.
    Wei Xiang, Zhoujun Zhu, Qisong Shang, Parhat Yasin, Yuanyuan Wu, Xinghua Song.
      Background: In this study, exosomes were engineered with anti-CD47 antibody and loaded with rifapentine to improve their ability to target macrophages for drug delivery. Methods: Exosomes from RAW264.7 cell supernatant were extracted by differential centrifugation, antibody-modified, and drug-loaded ultrasonically. After co-culturing with macrophages, transcriptomics and proteomics screened differentially expressed genes and proteins. Western Blot identified macrophage polarization, ELISA detected inflammatory indicators, and an apoptosis kit was used for fluorescence staining. Results: Transcriptome sequencing showed that 406 genes in the macrophages changed significantly, with pathways like TNF and NF-κB. Proteomics identified 7478 proteins, 433 with significant differences. Western Blot indicated M1 polarization. Fluorescence staining showed apoptosis in the antiMExo-RIF group. Conclusions: The study provides multi-omics evidence of the immune mechanism of the engineered exosome drug delivery system in inducing macrophage apoptosis, revealing potential molecular mechanisms and the great potential use of engineered exosomes in treating macrophage-related diseases.
    Keywords:  engineered exosomes; macrophage; proteomics; rifapentine; transcriptome sequencing
    DOI:  https://doi.org/10.3390/pharmaceutics17040494
  2. Mater Today Bio. 2025 Jun;32 101732
    An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity.
    Yurong Xiang, Qiang Liu, Kang Liu, Liuxian Chen, Fengjiao Chen, Tao Li, Siqi Li, Qiang Yu, Quan Lv, Zheng Xiang.
      Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant results. Artificial vectors are emerging as promising delivery systemts for RNA for gene therapy. In this study, a multi-drug therapy system was built based on a biodegradable exosome nano-platform exploiting the protective and low immunogenic properties of exosomes for RNA. This work aimed to accomplish the co-delivery of siRNA and 3-Bromopyruvic acid (3BP) on an exosome nanoplatform, enhancing targeting by coupling cetuximab (CTX) to exosome membranes, resulting in a new nanomedicine Exo@siRNA/3BP-CTX (ERBC) engineered exosomes. The synthesis conditions were optimized to obtain stable, safe, and effective nanomedicines. Successful targeting of tumors with CTX inhibited KRAS oncogene expression and significantly reduced glucose uptake by cancer cells. This enhanced the starvation therapy effect of the energy deprivation agent 3BP, thus promoting excessive autophagy activation in cells and doubling apoptosis. However, ERBC combined with CTX therapy restored cellular chemosensitivity to CTX. These findings indicate that engineered exosomes with dual therapeutic activities is a promising approach for treating refractory KRAS-mutant cancers.
    Keywords:  Cetuximab chemosensitivity; Colorectal cancer; Exosome; KRAS mutation; Starvation therapy
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101732
  3. Int J Nanomedicine. 2025 ;20 5137-5160
    Exosomes in Systemic Autoimmune Diseases: Recent Advances in Diagnostic Biomarkers and Therapeutic Applications.
    Xinchen Lv, Wendong Liu, Xue Zhou, Yu Yang, Wangqian Zhao, Linfeng Meng, Fenghuoyi Mu, Zhixiang Zhang, Shaohua Zhu, Shuai Zhang, Ying Wang.
      Systemic autoimmune diseases (SADs) encompass a spectrum of organ involvement, clinical heterogeneity, and therapeutic challenges meriting significant research. These conditions involve the immune system mistakenly attacking and damaging multiple body tissues and organs, leading to chronic inflammation and damage. Exosomes are nanoscale extracellular vesicles secreted by cells that modulate intercellular communication and immunity. Accumulating evidence indicates that exosomes have multifaceted roles in the pathogenesis of SADs through processes like cellular signaling, immune modulation, antigen presentation, and inflammatory response. The cargo of exosomes, such as proteins, miRNAs, and lipids, are vital determinants of cellular and humoral immunity. This review examines key signaling pathways in four common SADs, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome, and explores exosome as non-invasive biomarkers for diagnosis, disease monitoring, and therapeutic response prediction. Additionally, the therapeutic potential of mesenchymal stromal cells (MSCs) or various type of mesenchymal stem cells derived exosomes as cell-free immunotherapies for SADs is highlighted. Engineered exosomes, with enhanced targeting, bioavailability, low toxicity, are emerging as promising drug delivery vehicles. However, challenges such as high production costs, technical complexity, and inefficiency, along with the lack of standardized protocols, limit clinical implementation in SADs. A deeper understanding of exosome roles in SADs pathogenesis and innovative immunotherapies may provide valuable theoretical support for the diagnosis and treatment of these challenging conditions.
    Keywords:  MSC-therapy; biomarkers; exosomes; immunoregulation; systemic autoimmune diseases
    DOI:  https://doi.org/10.2147/IJN.S506221
  4. Mater Today Bio. 2025 Jun;32 101738
    Engineered exosomes improve the effects of curcumin on protecting mitochondria of neurons in Alzheimer's disease.
    Ya-Ning Ding, Mei-Qi Li, Jia-Yi Song, Pei-Pei Guan, Pu Wang.
      The synthetic DSPE-PEG2000-C3 peptide and DSPE-PEG2000-TPP were designed to modify the exosomes (EXO) by incubation, through which guide the C3/TPP-EXO to target the injured mitochondria of neurons. Then, C3/TPP-EXO was further used to encapsulate the curcumin (CUR) to enhance the solubility and bioavailability of the drug. By intravenously injected (i.v) into taup301s mutant transgenic (Tg) mice, C3/TPP-EXO facilitated the CUR to target the mitochondria of neurons and increase the entry efficiency of medication. To further reveal the mechanisms of drug entry, sodium azide (NaN3), an energy inhibitor, was used to treat HT22 cells. The results demonstrated that the entrance efficiency of the engineered EXO is significantly affected suggesting that C3/TPP-EXO may target mitochondria through energy routes. To deeply study the exact molecular mechanisms of C3/TPP-EXO-CUR in treating AD, RNA-Seq was used to identify the relevant molecules. Through GO annotation, many genes are enriched in the pathways of mitochondria functions. Based on these RNA-Seq data, C3/TPP-EXO-CUR showed neuroprotective effects via modulating the protein expression of Bcl-2, Bax and caspase-3 in HT22 cells. To further confirm the in vitro results, the in vivo results revealed that C3/TPP-EXO-CUR treatment inhibited the phosphorylation of tau and protected neurons by inhibiting the apoptotic genes, leading to improve the memory decline of taup301s mice. Collectively, the current study revealed the benefits and mechanisms of C3/TPP-EXO-CUR for treating AD, which might provide a novel and effective therapeutic approach for the disease.
    Keywords:  Curcumin; Exosome; Mitochondria; Synapse loss; Tau
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101738
  5. Microorganisms. 2025 Apr 04. pii: 823. [Epub ahead of print]13(4):
    Exosome-Modified AAV Gene Therapy Attenuates Autoimmune Hepatitis via Enhanced Regulatory T Cell Targeting and Immune Modulation.
    Wenwei Shao, Weilin Huang, Yixuan Wang, Helin Sima, Kai Ma, Rongtao Chen, Heqiao Han, Yixuan Yang, Yuchen Bao, Xiaolei Pei, Lei Zhang.
      Autoimmune hepatitis (AIH) is a chronic liver disorder driven by immune dysregulation, marked by reduced regulatory T cells (Tregs) and unchecked inflammation. Current therapies lack specificity and efficacy, necessitating novel approaches. This study explores gene therapy using exosome-associated adeno-associated virus (exo-AAV) to deliver the Foxp3 gene, aiming to restore Treg-mediated immune tolerance in AIH. We engineered exosomes expressing the CD4-targeting antibody on their surface, encapsulating AAV6/Foxp3, to enhance lymphoid cell specificity. In a ConA-induced murine AIH model, engineered exo-AAV administration significantly increased hepatic Treg proportions while reducing Th17 cells and inflammatory cytokines (IFN-γ, TNF-α, IL-6), compared to control groups (unmodified exo-AAV or empty exosomes). Liver histopathology and serum ALT levels also improved in engineered exo-AAV treated mice. Mechanistically, engineered exo-AAV demonstrated superior targeting via CD4 binding, validated by immunofluorescence and nanoparticle tracking. Despite transient reductions in splenic Tregs, localized hepatic immune modulation underscored exo-AAV's efficacy. These findings highlight engineered exo-AAV as a promising strategy for precision gene therapy in AIH, overcoming limitations of traditional AAV delivery by enhancing lymphocyte-specific transduction and immune balance restoration. This approach presents a novel therapeutic avenue for systemic autoimmune diseases reliant on Treg reinforcement.
    Keywords:  Foxp3; autoimmune hepatitis; exosome-associated AAV; gene therapy; immune modulation; regulatory T cells
    DOI:  https://doi.org/10.3390/microorganisms13040823
  6. Int J Nanomedicine. 2025 ;20 5267-5289
    Human Mesenchymal Stem Cell-Derived Exosomes as Engineering Vehicles of Daunorubicin for Targeted c-Mpl+ AML Therapy.
    Chunmou Li, Yuchen Wen, Jiasheng Wang, Lindi Li, Yue He, Yucai Cheng, Junru Chen, Junbin Huang, Cheng Ouyang, Yong Liu, Ruizhi Zhou, Haisheng Chen, Fei Li, Qiqi Guo, Yun Chen, Chun Chen, Qing Zhang.
       Background: Acute myeloid leukemia (AML) is a highly heterogeneous disease with poor therapeutic outcomes and overall prognosis, particularly in c-Mpl+ AML. c-Mpl, a proto-oncogene, is expressed at significantly higher levels in AML compared to normal human tissue cells. This study aimed to develop a type of targeted exosomes (Exos) capable of delivering anticancer drugs directly to c-Mpl+ AML cells.
    Methods: Human umbilical cord mesenchymal stem cells (hUCMSCs) were isolated as the source of Exos. Fusion CD63 proteins with varying numbers of thrombopoietin (TPO)-mimic peptides, designed to target c-Mpl, were bioengineered to be expressed on the membranes of hUCMSCs and their derived Exos. The targeting capability of the fusion proteins was assessed using the DUAL membrane system, fluorescence resonance energy transfer efficiency, and endocytosis assays. After encapsulating the anticancer drug daunorubicin (DNR), these targeted Exos were evaluated for their ability to eliminate c-Mpl+ AML cells. Safety and efficacy were further tested in a mouse AML model.
    Results: Our findings showed that the engineered hUCMSCs-derived Exos demonstrated excellent targeting ability to c-Mpl and a strong propensity for endocytic uptake by c-Mpl+ AML cells. Among the engineered Exos, those with the fusion protein containing three TPO-mimic peptides (CD63-mTPO3), named as m3Exos, exhibited the highest binding affinity for c-Mpl. When loaded with DNR, these engineered Exos (m3Exos@DNR) effectively eliminated c-Mpl+ AML cells in both in vitro and in vivo experiments. Furthermore, safety assessments revealed that therapy-related toxicities were within acceptable limits and associated with manageable side effects.
    Conclusion: In summary, our results suggest engineered Exos as a highly effective targeted drug delivery vehicle for eliminating c-Mpl+ AML cells while maintaining a favorable safety profile. These findings also provide valuable insights for developing therapeutic strategies for AML and other tumors characterized by specific membrane protein expression.
    Keywords:  AML; c-Mpl; engineering; exosome; targeted therapy
    DOI:  https://doi.org/10.2147/IJN.S511713
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