bims-engexo 2025-01-26 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–01–26
nine papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

EXOTLR1/2-STING: A Dual-Mechanism Stimulator of Interferon Genes Activator for Cancer Immunotherapy.
Emerging Strategies for Revascularization: Use of Cell-Derived Extracellular Vesicles and Artificial Nanovesicles in Critical Limb Ischemia.
Exosomes and exosomal miRNAs mediate the beneficial effects of exercise in ischemic stroke.
Engineered Extracellular Vesicles Modified by Angiopep-2 Peptide Promote Targeted Repair of Spinal Cord Injury and Brain Inflammation.
Engineered Extracellular Vesicles from Antler Blastema Progenitor Cells: A Therapeutic Choice for Spinal Cord Injury.
Exosomes and microRNAs as mediators of the exercise.
Navigating liver cancer: Precision targeting for enhanced treatment outcomes.
Rigorous process for isolation of gut-derived extracellular vesicles and the effect on latent HIV.
Exosome-loading miR-205: a two-pronged approach to ocular neovascularization therapy.

ACS Nano. 2025 Jan 23.

EXOTLR1/2-STING: A Dual-Mechanism Stimulator of Interferon Genes Activator for Cancer Immunotherapy.

Tian-Yang Wang, Hong-Guo Hu, Lang Zhao, Shao-Hua Zhuo, Jing-Yun Su, Geng-Hui Feng, Yan-Mei Li.

  As natural agonists of the stimulator of interferon genes (STING) protein, cyclic dinucleotides (CDNs) can activate the STING pathway, leading to the expression of type I interferons and various cytokines. Efficient activation of the STING pathway in antigen-presenting cells (APCs) and tumor cells is crucial for antitumor immune response. Tumor-derived exosomes can be effectively internalized by APCs and tumor cells and have excellent potential to deliver CDNs to the cytoplasm of APCs and tumor cells. Here, we leverage tumor exosomes as a delivery platform, designing an EXOTLR1/2-STING loaded with CDNs. To achieve efficient loading of CDNs onto exosomes, we chemically conjugated CDNs with Pam3CSK4, a compound featuring multiple fatty acid chains, resulting in Pam3CSK4-CDGSF. Utilizing the high lipophilicity of Pam3CSK4, Pam3CSK4-CDGSF could be efficiently loaded onto the exosomes through simple incubation. Moreover, as an agonist for Toll-like receptor 1/2, Pam3CSK4 also exhibits robust immunological synergistic effects in conjunction with CDNs. EXOTLR1/2-STING effectively induced the activation of APCs and triggered tumor cell death, producing a favorable antitumor therapeutic effect. It also demonstrated significant synergistic effects with immune checkpoint therapies.

Keywords:  STING agonist; Toll-like Receptor 1/2; cancer immunotherapy; cyclic dinucleotide; delivery; engineered exosomes

DOI:  https://doi.org/10.1021/acsnano.4c18056
Bioengineering (Basel). 2025 Jan 20. pii: 92. [Epub ahead of print]12(1):

Emerging Strategies for Revascularization: Use of Cell-Derived Extracellular Vesicles and Artificial Nanovesicles in Critical Limb Ischemia.

Vijay Murali Ravi Mythili, Ramya Lakshmi Rajendran, Raksa Arun, Vasanth Kanth Thasma Loganathbabu, Danyal Reyaz, ArulJothi Kandasamy Nagarajan, Byeong-Cheol Ahn, Prakash Gangadaran.

  Critical limb ischemia (CLI) poses a substantial and intricate challenge in vascular medicine, necessitating the development of innovative therapeutic strategies to address its multifaceted pathophysiology. Conventional revascularization approaches often fail to adequately address the complexity of CLI, necessitating the identification of alternative methodologies. This review explores uncharted territory beyond traditional therapies, focusing on the potential of two distinct yet interrelated entities: cell-derived extracellular vesicles (EVs) and artificial nanovesicles. Cell-derived EVs are small membranous structures naturally released by cells, and artificial nanovesicles are artificially engineered nanosized vesicles. Both these vesicles represent promising avenues for therapeutic intervention. They act as carriers of bioactive cargo, including proteins, nucleic acids, and lipids, that can modulate intricate cellular responses associated with ischemic tissue repair and angiogenesis. This review also assesses the evolving landscape of CLI revascularization through the unique perspective of cell-derived EVs and artificial nanovesicles. The review spans the spectrum from early preclinical investigations to the latest translational advancements, providing a comprehensive overview of the current state of research in this emerging field. These groundbreaking vesicle therapies hold immense potential for revolutionizing CLI treatment paradigms.

Keywords:  critical limb ischemia; extracellular vesicles; nanovesicles; regenerative medicine; revascularization

DOI:  https://doi.org/10.3390/bioengineering12010092
Int J Sports Med. 2025 Jan 20.

Exosomes and exosomal miRNAs mediate the beneficial effects of exercise in ischemic stroke.

Xuefeng Tan, Zhimin Ding, Lizhen Shi, Ruonan Wu.

Ischemic stroke is an acute cerebrovascular disease that is one of the leading causes of death and neurological disorders worldwide. Exosomes are a novel class of intercellular signaling regulators containing cell-specific proteins, lipids, and nucleic acids that transmit messages between cells and tissues. MicroRNAs are regulatory non-coding ribonucleic acids that are usually present in exosomes as signaling molecules. Studies have shown that exosomes and exosomal microRNAs can improve the prognosis of ischemic stroke by inhibiting the inflammatory response, reducing apoptosis, improving the imbalance of oxidative and antioxidant systems, and regulating cellular autophagy, among other processes. Previous studies have shown that exercise training can exert neuroprotective effects on ischemic stroke by promoting the release of exosomes and regulating the expression of exosomal microRNAs, which in turn regulate multiple signaling pathways. Exosomes and exosomal microRNAs may be key targets for exercise to promote cerebrovascular health. Therefore, the study of exercise-mediated exosomes and their microRNAs may provide new perspectives for exploring the mechanism of exercise intervention in the prevention and treatment of ischemic stroke.

DOI: https://doi.org/10.1055/a-2500-5620
ACS Nano. 2025 Jan 24.

Engineered Extracellular Vesicles Modified by Angiopep-2 Peptide Promote Targeted Repair of Spinal Cord Injury and Brain Inflammation.

Guang Kong, Jie Liu, Juan Wang, Xiaohu Yu, Cong Li, Mingyang Deng, Minhao Liu, Siming Wang, Chunming Tang, Wu Xiong, Jin Fan.

  Engineered extracellular vesicles play an increasingly important role in the treatment of spinal cord injury. In order to prepare more effective engineered extracellular vesicles, we biologically modified M2 microglia. Angiopep-2 (Ang2) is an oligopeptide that can target the blood-brain barrier. Through single-cell sequencing and immunofluorescence experiments, we confirmed that the expression of LRP-1, the targeted receptor of Ang2, was elevated after spinal cord injury. Subsequently, we integrated the Ang2 peptide segment into M2 microglia to obtain Ang2-EVs, which could successfully target the site of spinal cord injury. However, in order to improve the function of Ang2-EVs, we pretreated M2 microglia with melatonin, which has anti-inflammatory effects, to obtain M-Ang2-EVs. The results of single-nucleus sequencing of the mouse spinal cord verified that neurons and OPCs gradually transformed into subtypes related to nerve repair functions after treatment with M-Ang2-EVs. This is consistent with the sequencing and enrichment analysis of miRNAs contained in M-Ang2-EVs. We further verified through experiments that M-Ang2-EVs can promote microglia/macrophages to phagocytose sphingomyelin, promote axon remyelination and axon elongation, and maintain the integrity of the blood-spinal barrier. Since Ang2 can also target the blood-brain barrier, we found that M-Ang2-EVs can also reduce brain inflammation that results from spinal cord injury. Our study applied the Angiopep-2 peptide to spinal cord injury to enhance the targeting of injured cells, and successfully construct engineered extracellular vesicles that can target the spinal cord injury site and the brain.

Keywords:  angiopep-2; axonal regeneration; cerebral inflammation; engineered extracellular vesicles; melatonin; spinal cord injury

DOI:  https://doi.org/10.1021/acsnano.4c14675
ACS Nano. 2025 Jan 22.

Engineered Extracellular Vesicles from Antler Blastema Progenitor Cells: A Therapeutic Choice for Spinal Cord Injury.

Shijie Yang, Borui Xue, Yongfeng Zhang, Haining Wu, Beibei Yu, Shengyou Li, Teng Ma, Xue Gao, Yiming Hao, Lingli Guo, Qi Liu, Xueli Gao, Yujie Yang, Zhenguo Wang, Mingze Qin, Yunze Tian, Longhui Fu, Bisheng Zhou, Luyao Li, Jianzhong Li, Shouping Gong, Bing Xia, Jinghui Huang.

  Deer antler blastema progenitor cells (ABPCs) are promising for regenerative medicine due to their role in annual antler regeneration, the only case of complete organ regeneration in mammals. ABPC-derived signals show great potential for promoting regeneration in tissues with limited natural regenerative ability. Our findings demonstrate the capability of extracellular vesicles from ABPCs (EVsABPC) to repair spinal cord injury (SCI), a condition with low regenerative capacity. EVsABPC significantly enhanced the proliferation of neural stem cells (NSCs) and activated neuronal regenerative potential, resulting in a 5.2-fold increase in axonal length. Additionally, EVsABPC exhibited immunomodulatory effects, shifting macrophages from M1 to M2. Engineered with activated cell-penetrating peptides (ACPPs), EVsABPC significantly outperformed EVs from rat bone marrow stem cells (EVsBMSC) and neural stem cells (EVsNSC), promoting a 1.3-fold increase in axonal growth, a 30.6% reduction in neuronal apoptosis, and a 2.6-fold improvement in motor function recovery. These findings support ABPC-derived EVs as a promising therapeutic candidate for SCI repair.

Keywords:  antler blastema progenitor cells; axonal growth; extracellular vesicles; neural stem cells; spinal cord injury

DOI:  https://doi.org/10.1021/acsnano.4c10298
Eur J Med Res. 2025 Jan 19. 30(1): 38

Exosomes and microRNAs as mediators of the exercise.

Haoyuan Li, Guifang Liu, Bing Wang, Mohammad Reza Momeni.

  MicroRNAs (miRNAs), also known as microribonucleic acids, are small molecules found in specific tissues that are essential for maintaining proper control of genes and cellular processes. Environmental factors, such as physical exercise, can modulate miRNA expression and induce targeted changes in gene transcription. This article presents an overview of the present knowledge on the principal miRNAs influenced by physical activity in different tissues and bodily fluids. Numerous research projects have emphasized the significant impact of miRNAs on controlling biological changes brought about by physical activity. These molecules play main roles in important processes such as the growth of skeletal muscle and heart muscle cells, the creation of mitochondria, the development of the vascular system, and the regulation of metabolism. Studies have shown that physical exertion utilizes the contributions of miR-1, miR-133, miR-206, miR-208, and miR-486 to revitalize and restore skeletal muscle tissue. Moreover, detecting alterations in miRNA levels and connecting them to the specific outcomes of various exercise routines and intensities can act as indicators for physical adaptation and the reaction to physical activity in long-term diseases. Numerous studies have confirmed that extracellular vesicles (EVs) which composed of different members such as exosomes have the ability to reduce inflammation through the activation of the nuclear factor kappa B (NF-κB pathway. Furthermore, physical activity greatly affects the levels of specific miRNAs present in exosomes derived from skeletal muscle. Therefore, exosomal miRNAs target some pathways that are related to growth and development, such asWnt/β-catenin, PI3K/AKT, and insulin-like growth factor 1 (IGF1). Exercise-induced exosomes have also been identified as important mediators in promoting beneficial effects throughout the body. The aim of this review is to summarize the effect of exercise on the function of miRNAs and exosomes.

Keywords:  Biomarker; Epigenetic; Exercise; Exosome; MicroRNA

DOI:  https://doi.org/10.1186/s40001-025-02273-4
Drug Deliv Transl Res. 2025 Jan 23.

Navigating liver cancer: Precision targeting for enhanced treatment outcomes.

Ankit Jain, Ashwini Kumar Mishra, Pooja Hurkat, Satish Shilpi, Nishi Mody, Sanjay Kumar Jain.

  Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.

Keywords:  Cancer; Hepatocellular carcinoma; Liver; Nanocarriers; Targeting

DOI:  https://doi.org/10.1007/s13346-024-01780-x
bioRxiv. 2025 Jan 09. pii: 2025.01.09.632234. [Epub ahead of print]

Rigorous process for isolation of gut-derived extracellular vesicles and the effect on latent HIV.

Nneoma C J Anyanwu, Lakmini S Premadasa, Wasifa Naushad, Bryson C Okeoma, Mohan Mahesh, Chioma M Okeoma.

Aim: Extracellular particles (EPs) are produced/secreted by cells from all domains of life and are present in all body fluids, brain, and gut. EPs consist of extracellular vesicles (EVs) made up of exosomes, microvesicles, and other membranous vesicles; and extracellular condensates (ECs) that are non-membranous carriers of lipid-protein-nucleic acid aggregates. The purity of EVs|ECs, which ultimately depends on the isolation method used to obtain them is critical, particularly EVs|ECs from the gastrointestinal (GI) tract that is colonized by a huge number of enteric bacteria. Therefore, identifying GI derived EVs|ECs of bacterial and host origin may serve as a window into the pathogenesis of diseases and as a potential therapeutic target.
Methods: Here, we describe the use of high-resolution particle purification liquid chromatography (PPLC) gradient-bead-column integrated with polyvinylpolypyrrolidone (PVPP)-mediated extraction of impurities to isolate GI-derived EPs.
Results and Conclusion: PVPP facilitates isolation of pure and functionally active, non-toxic EVs ColEVs from colonic contents. ColEVs are internalized by cells and they activate HIV LTR promoter. In the absence of PVPP, ColEVs have a direct reductive potential of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) absorbance in a cell-free system. Assessment of the origin of ColEVs reveals that they are composed of both bacteria and host particles. This protocol requires ∼12 hours (5 hours preprocessing, 7 hours isolation) to complete and should be used to purify EVs from sources contaminated with microbial agents to improve rigor. Additionally, this protocol provides a robust tool for researchers and clinicians investigating GI-derived EVs and the translational use of GI-derived EVs for diagnostic and therapeutic use.
Highlight: ColEVs but not ColECs are present in colonic content (GI tract) and can be isolated with gradient or single bead PPLC column.ColEVs isolated without PVPP are toxic to cells and they have a direct reductive potential of MTT. Addition of PVPP treatment in the isolation protocol results in clean and non-toxic ColEVs that transactivate the HIV LTR promoter.

DOI: https://doi.org/10.1101/2025.01.09.632234
J Nanobiotechnology. 2025 Jan 22. 23(1): 36

Exosome-loading miR-205: a two-pronged approach to ocular neovascularization therapy.

Hui-Ying Zhang, Qiu-Yang Zhang, Qing Liu, Si-Guo Feng, Yan Ma, Feng-Sheng Wang, Yue Zhu, Jin Yao, Biao Yan.

  Pathological neovascularization is a hallmark of many vision-threatening diseases. However, some patients exhibit poor responses to current anti-VEGF therapies due to resistance and limited efficacy. Recent studies have highlighted the roles of noncoding RNAs in various biological processes, paving the way for RNA-based therapeutics. In this study, we report a marked down-regulation of miR-205 under pathological conditions. miR-205 potently inhibits endothelial cell functions critical for pathological neovascularization, including proliferation, migration, and tube formation. Furthermore, miR-205 strengthens the endothelial barrier, thereby reducing vascular leakage. In mouse models of retinal and choroidal neovascularization, miR-205 administration effectively suppresses abnormal blood vessel formation and leakage. Mechanistically, miR-205 directly targets VEGFA and ANGPT2, which are key drivers of pathological neovascularization. To improve delivery, we successfully loaded miR-205 into exosomes derived from mesenchymal stem cells. This innovative approach avoids cytotoxicity while preserving therapeutic efficacy in both cellular and animal models. Collectively, our findings highlight miR-205 as a promising therapeutic for ocular neovascularization, with exosome delivery offering a novel and efficient strategy for treating vision-threatening vascular diseases.

Keywords:  ANGPT2; Exosomes; Ocular neovascularization; VEGFA; miR-205

DOI:  https://doi.org/10.1186/s12951-024-03079-y