bims-engexo 2025-03-23 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–03–23
seven papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Application of engineered exosomes in tumor therapy.
A novel function for exosomes in depression.
Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.
Exosome technology: A novel and effective drug delivery system in the field of cancer therapy.
Intranasal delivery of engineered extracellular vesicles promotes neurofunctional recovery in traumatic brain injury.
Leveraging engineered yeast small extracellular vesicles serve as multifunctional platforms for effectively loading methyl salicylate through the "esterase-responsive active loading" strategy.
KRAS G12D -Specific Targeting with Engineered Exosomes Reprograms the Immune Microenvironment to Enable Efficacy of Immune Checkpoint Therapy in PDAC Patients.

Am J Transl Res. 2025 ;17(2): 736-747

Application of engineered exosomes in tumor therapy.

Chunhui Ma, Wei Tang, Jiaye Wang, Shiyu Yang, Jin Hou, Meng Guo, Lu Hao.

  Malignant tumors pose a significant threat to human health, and conventional cancer therapies are limited by inadequate targeting, leading to severe side effects. Exosomes, as extracellular vesicles mediating intercellular communication, exhibit advantages such as low immunogenicity, high biocompatibility, and low toxicity. After modification, engineered exosomes can be employed as targeted delivery vehicles in tumor therapy. This review summarizes the cellular origin, production methods, engineering strategies, and drug-loading routes of engineered exosomes, discusses their applications in cancer treatment, and delves into the challenges and issues in translating engineered exosomes to clinical practice, aiming to provide insights for exosome engineering research.

Keywords:  Engineered exosomes; clinical applications; tumor therapy

DOI:  https://doi.org/10.62347/KIXF4662
Life Sci. 2025 Mar 13. pii: S0024-3205(25)00192-4. [Epub ahead of print] 123558

A novel function for exosomes in depression.

Qingying Yu, Shuyi Ye, Mengxue Chen, Peng Sun, Ning Weng.

  Exosomes are a class of extracellular vesicles that encompass a diverse array of bioactive molecules, including proteins, lipids, mRNA, and microRNA(miRNA). Virtually all cell types release exosomes under both physiological and pathological conditions. In addition to electrical and chemical signals, exosomes are an alternative route of signaling between cells in the brain. In the brain, they are involved in processes such as synaptic plasticity, neuronal stress response, intercellular communication, and neurogenesis. A number of studies have shown that exosomes regulate the occurrence and development of depression by participating in the regulation of hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, immune inflammatory response and other mechanisms, showing that they may become potential biological agents for the diagnosis and treatment of depression. In addition, exosomes have the ability to easily cross the blood-brain barrier, making them ideal drug or molecular delivery tools for the central nervous system. Engineered exosomes have good brain targeting ability, and their research in central nervous system diseases has begun to emerge. However, the molecular pathways involved in the pathogenesis of depression remain unknown, and further studies are needed to fully understand the role of exosomes in the development or improvement of depression. Therefore, in this review, we mainly focus on the diagnostic performance and therapeutic effect of exosomes in depression, and explore the advantages of exosomes as biomarkers and gene delivery vectors for depression.

Keywords:  Central nervous system; Depression; Exosomes; Extracellular vesicles

DOI:  https://doi.org/10.1016/j.lfs.2025.123558
Mol Neurobiol. 2025 Mar 17.

Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.

Sam Dehghani, Ozgecan Ocakcı, Pars Tan Hatipoglu, Veli Cengiz Özalp, Atakan Tevlek.

  Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.

Keywords:  ALS; Alzheimer’s disease; Biomarkers; Blood–brain barrier; Exosomes; Neurodegenerative diseases; Parkinson’s disease; Therapeutic agents

DOI:  https://doi.org/10.1007/s12035-025-04825-5
World J Gastrointest Oncol. 2025 Mar 15. 17(3): 101857

Exosome technology: A novel and effective drug delivery system in the field of cancer therapy.

Jia-Xin Geng, Yao-Fan Lu, Jing-Nan Zhou, Biao Huang, Yuan Qin.

  In this article, we revisit an article, which specifically focuses on the utilization of exosomes derived from human bone marrow mesenchymal stem cells (MSCs) for targeted delivery of gemcitabine in pancreatic cancer treatment. The experimental results demonstrated that the exosome-based drug delivery system derived from MSCs significantly augmented apoptosis in pancreatic cancer cells. The biocompatibility, targeting specificity, and low immunogenicity of exosomes render them as optimal carriers for drug delivery, enabling precise administration of therapeutics to diseased tissues while mitigating adverse effects, thereby achieving targeted treatment of cancer cells and significantly enhancing anti-tumor efficacy. However, the clinical application of exosome drug delivery platforms in oncology still presents challenges, necessitating further optimization to ensure their stability and efficacy. This study focuses on elucidating the advantages of exosomes as a drug delivery platform, exploring the utilization of MSC-derived exosomes in oncology therapy, and discussing their potential and future directions in cancer treatment.

Keywords:  Drug delivery; Exosomes; Gemcitabine; Mesenchymal stem cells; Tumor therapy

DOI:  https://doi.org/10.4251/wjgo.v17.i3.101857
J Nanobiotechnology. 2025 Mar 21. 23(1): 229

Intranasal delivery of engineered extracellular vesicles promotes neurofunctional recovery in traumatic brain injury.

Pengtao Li, Sishuai Sun, Xingyu Zhu, Xiaoyu Liu, Rui Yin, Yihao Chen, Jianbo Chang, Liguo Ye, Jingxi Gao, Xiaoyan Zhao, Houshi Xu, Yue Wang, Wei Zuo, Zhao Sun, Shihua Wang, Xiao Zhang, Junji Wei, Robert Chunhua Zhao, Qin Han.

  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.

Keywords:  Engineered extracellular vesicles; NF-κB; Neurofunctional recovery; Neuroinflammation; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12951-025-03181-9
Eur J Pharm Biopharm. 2025 Mar 18. pii: S0939-6411(25)00073-6. [Epub ahead of print] 114696

Leveraging engineered yeast small extracellular vesicles serve as multifunctional platforms for effectively loading methyl salicylate through the "esterase-responsive active loading" strategy.

Tianhao Li, Yun Zhou, Haoran Wang, Junfeng Wang, Rong Lu.

  Small extracellular vesicles (sEVs) are a promising vehicle for drug delivery because of their good biocompatibility and nontoxicity. The drug loading and encapsulation efficiencies of them are not satisfactory. This is especially the case when drugs are loaded by co-incubation. In this situation, as the difference in drug concentration between the inside and outside of the membrane of ordinary sEVs decreases, the drugs cannot diffuse efficiently into the inside of the vesicles. As a result, the drug loading efficiency is low. In this study, engineered yeast-derived small extracellular vesicles derived from Pichia pastoris X33 (XPP-sEVs) engineered with carboxylesterase 1 (CES1) were constructed using the "esterase-responsive active loading" method, which is based on the concept of prodrug design and guided by the strategy of immobilized enzymes, to improve the loading efficiency of methyl salicylate (MS) to about twice as much. This was achieved by engineering the CES1-contained small extracellular vesicles to catalyze the esterase hydrolysis reaction of MS to establish a continuous MS transmembrane concentration gradient for efficient loading of the active drugs, including methyl salicylate and its hydrolyzed active product salicylic acid. The results showed that the enzyme activity of the CES1-sEVs group finally reached 7.88 ± 0.43 U/mL, and the drug loading efficiency was about doubled. The results of drug release from the engineered extracellular vesicles showed that the release of the drug reached equilibrium around 100 min-2 h, during which there was no sudden release of the MS, and the final amount of the drug released could be increased by 12.34 % compared with the emulsion dosage form of the MS. Overall, the CES1-sEVs prepared in this study significantly improved the drug-loading efficiency of MS without affecting the anti-inflammatory activity of MS. The MS-CES1-sEVs prepared in this study are non-toxic and have a bright application prospect in the treatment of skin inflammation.

Keywords:  Drug delivery; Esterase-responsive active loading; Methyl salicylate; Pichia pastoris X33; Small extracellular vesicles; Yeast

DOI:  https://doi.org/10.1016/j.ejpb.2025.114696
medRxiv. 2025 Mar 06. pii: 2025.03.03.25322827. [Epub ahead of print]

KRAS G12D -Specific Targeting with Engineered Exosomes Reprograms the Immune Microenvironment to Enable Efficacy of Immune Checkpoint Therapy in PDAC Patients.

Valerie S LeBleu, Brandon G Smaglo, Krishnan K Mahadevan, Michelle L Kirtley, Kathleen M McAndrews, Mayela Mendt, Sujuan Yang, Ana S Maldonado, Hikaru Sugimoto, Maria E Salvatierra, Luisa M Solis Soto, Rick Finch, Mihai Gagea, Adam C Fluty, Steve J Ludtke, J Jack Lee, Abhinav K Jain, Gauri Varadhachary, Rachna T Shroff, Anirban Maitra, Elizabeth Shpall, Raghu Kalluri, Shubham Pant.

Oncogenic KRAS drives initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with Kras G12D specific siRNA (iExoKras G12D ) reveal impressive biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKras G12D in the iEXPLORE (iExoKras G12D in Pancreatic Cancer) Phase I study employed a classical 3+3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) ( NCT03608631 ). Patients with advanced metastatic disease were enrolled after failure of multiple lines of therapy. iExoKras G12D therapy was well-tolerated with no reported dose-limiting toxicity with some cases of stable disease response, and maximum tolerated infusion was not reached even at the highest dose. Downregulation of KRAS G12D DNA and suppression of phopho-Erk was documented with increased intratumoral in CD8 + T cell infiltration in patient samples upon treatment. The CD8 + T cell recruitment priming by iExoKras G12D informed on potential efficacy of immune checkpoint therapy and lead to validation testing in preclinical PDAC models. Combination therapy of iExoKras G12D and anti-CTLA-4 antibodies, but not anti-PD1, revealed robust anti-tumor efficacy via FAS mediated CD8 + T cell anti-tumor activity. This first-in-human, precision medicine clinical trial offers new insights into priming of immunotherapy by oncogenic Kras inhibitor and an opportunistic combination therapy for PDAC patients.

DOI: https://doi.org/10.1101/2025.03.03.25322827