bims-engexo 2025-02-16 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–02–16
eight papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Targeted inhibition of ferroptosis in bone marrow mesenchymal stem cells by engineered exosomes alleviates bone loss in smoking-related osteoporosis.
Exosomal ALKBH5 Alleviates Vascular Calcification by Suppressing Cell Apoptosis via m6A-Modified GSDME.
Acidic Conditions Promote Clustering of Cancer Cell Derived Extracellular Vesicles and Enhance their Fusion with Synthetic Liposomes.
Serum exosomal miR-454-3p contributes to malignant progression of lung cancer by inhibiting HHEX.
Roles, Functions, and Pathological Implications of Exosomes in the Central Nervous System.
Controlled delivery of HIF-1α via extracellular vesicles with collagen-binding activity for enhanced wound healing.
Engineered extracellular vesicles with sequential cell recruitment and osteogenic functions to effectively promote senescent bone repair.
Glycoengineered stem cell-derived extracellular vesicles for targeted therapy of acute kidney injury.

Mater Today Bio. 2025 Apr;31 101501

Targeted inhibition of ferroptosis in bone marrow mesenchymal stem cells by engineered exosomes alleviates bone loss in smoking-related osteoporosis.

Yao Wang, Lin Sun, Zhenglin Dong, Tianyu Zhang, Leining Wang, Yihui Cao, Hui Xu, Chenglei Liu, Bo Chen.

Smoking-related osteoporosis (SROP) is characterized by reduced bone mass, primarily due to the accumulation of tobacco-derived toxins. This study demonstrates the activation of ferroptosis and reactive oxygen species (ROS)-related pathways in the bone marrow mesenchymal stem cells (BMSCs) of SROP mice. Here, we integrated genetic engineering and bone-targeting peptide modification to develop innovative bone-targeting engineered exosomes. Using genetic engineering techniques, we introduced α-1,3-fucosyltransferase 6 (Fut6), a key protein involved in prostate cancer bone metastasis, and identified exosomes expressing Fut6 (F6-exo) with bone-targeting capabilities. Additionally, we modified these exosomes with a bone-targeting peptide, (AspSerSer)6, to synthesize F6-(DSS)6-exo. F6-(DSS)6-exo enabled the targeted delivery of curcumin, restoring the osteogenic differentiation potential of BMSCs and mitigating bone loss in SROP mouse models. In summary, this study highlights the combination of genetic engineering and hydrophobic diacylglycerol insertion as a novel targeted therapeutic approach for SROP.

DOI: https://doi.org/10.1016/j.mtbio.2025.101501
Drug Dev Res. 2025 Feb;86(1): e70065

Exosomal ALKBH5 Alleviates Vascular Calcification by Suppressing Cell Apoptosis via m6A-Modified GSDME.

Guian Xu, Qingman Li, Lijie Zhu, Tingjie Yang, Yapan Yang, Honghui Yang.

  This study aimed to explore the function and regulatory mechanism of ALKBH5 in the progression of coronary artery calcification. Human aortic vascular smooth muscle cells (HA-VSMCs) were treated with inorganic phosphate (Pi) and exosomes derived from bone marrow mesenchymal stem cell (BMSC) carrying ALKBH5, a GSDME overexpression vector or si-GSDME. The morphology and size of the exosomes were assessed using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Calcium deposition was measured using Alizarin red staining and cell pyroptosis was evaluated using Hoechst 33342/PI staining. The association between ALKBH5 and m6A modifications was confirmed by methylated-RNA immunoprecipitation assay (MeRIP) and dot blot assays. The expression levels of ALKBH5 and GSDME were quantified by quantitative real-time polymerase chain reaction (qRT-PCR), and protein levels were quantified by western blot. BMSCs-derived exosomes reduced calcium deposition and cell pyroptosis in Pi-treated HA-VSMCs. Exosomes containing ALKBH5 overexpression inhibited high mobility group box 1 (HMGB1) and cell apoptosis, thereby promoting vascular calcification, whereas ALKBH5 knockdown in exosomes exerted the opposite effect on calcification development. Additionally, ALKBH5 was found to regulate the m6A modification of GSDME. Overexpression of GSDME reversed the effects of ALKBH5 in exosomes on HMGB1 expression and cell apoptosis. Exosomal ALKBH5 mitigated HMGB1 expression and cell pyroptosis by modulating the m6A modification of GSDME, thus influencing the progression of coronary artery calcification.

Keywords:  ALKBH5; GSDME; calcification; m6A modification; pyroptosis

DOI:  https://doi.org/10.1002/ddr.70065
Langmuir. 2025 Feb 12.

Acidic Conditions Promote Clustering of Cancer Cell Derived Extracellular Vesicles and Enhance their Fusion with Synthetic Liposomes.

William S Fisher, Jessica Douglas, Sherwin Roshan, Ramon Perez, Sophia Wei, Logan Roberts, Kai K Ewert, Cyrus R Safinya.

Extracellular vesicles (EVs) are endogenous vesicles secreted by cells. Exosomes (30-150 nm), are a subset of EVs playing key roles in intercellular communication. Exosomes show promise as cancer chemotherapeutic drug delivery vehicles given their low immunogenicity and cell-specific cytosolic delivery of their contents. However, inefficient drug loading limits their therapeutic application. To address this, methods for the fusion of EVs with therapeutic drug-loaded synthetic liposomes have been developed. While more efficient than passive incubation of EVs with liposomes, these risk either damage to EV membrane proteins or contamination of the EV-liposome hybrids with residual depletant molecules, which can cause side effects or hinder content delivery. Here, we present a new, weakly perturbative method, which uses acidic conditions (pH 5) to enhance the fusion of EVs and synthetic, neutral liposomes (NLs) compared to passive incubation in pH 7.4 at 37 °C. An adapted Forster resonance energy transfer (FRET) based lipid mixing assay confirms that fusion is enhanced with this method, albeit less efficiently than with depletant-induced fusion. This significant finding implies that lipid-only synthetic liposomes can fuse with EVs, creating EV-liposome hybrids under relevant temperature and pH conditions, without nonlipidic components, such as fusogenic amphipathic peptides, added to the synthetic liposomes. Remarkably, differential interference contrast (DIC) and fluorescence microscopy show that this enhanced fusion corresponds with the clustering of mixtures of EVs and NLs, or EVs alone, in acidic but not neutral pH conditions. The findings support a hypothesis that content release from EVs in early to late endocytic environments may be a combination of protein-protein clustering interactions and a lipidic component. Further, this study provides a novel method for enhanced fusion of EVs and liposomes, which is expected to preserve EV membrane proteins and functionality toward the development of therapeutic hybrid drug delivery vehicles in nanomedicine applications.

DOI: https://doi.org/10.1021/acs.langmuir.4c04297
Mol Cell Probes. 2025 Feb 08. pii: S0890-8508(25)00012-X. [Epub ahead of print] 102019

Serum exosomal miR-454-3p contributes to malignant progression of lung cancer by inhibiting HHEX.

Gangqin Hu, Peng Cai, Jingjing Li, Liuyang Yu, Bolin Zhao, Guiming Chen.

   BACKGROUND: Lung cancer is a common cancer. Exosomes are emerging mediators of intercellular communication, and miRNAs serve a crucial position in cancer progression. This project intends to discover whether exosomal miR-454-3p affects tumor progression and its underlying mechanisms.
METHODS: Exosomes were isolated utilizing ultracentrifugation. The exosomal biomarkers level was monitored by western blot (WB). The miR-454-3p levels were assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and HHEX expression were detected by qRT-PCR and WB. Cell growth and metastasis were detected through CCK-8, colony formation assay and transwell. Meanwhile, the dual luciferase reporter system and immunoprecipitation (RIP) assay was applied to clarify the interactions between miR-454-3p and HHEX.
RESULTS: We successfully isolated serum exosomes from NSCLC patients. Then, our team discovered that miR-454-3p was elevated in serum-derived exosomes from NSCLC patients. Functional analysis disclosed that exosomes accelerated NSCLC cell proliferation and metastasis. Silencing of exosomal miR-454-3p hindered NSCLC cell proliferation and metastasis. Subsequently, the starbase database declared that miR-454-3p was interacted with HHEX. HHEX overexpression reversed the promotion of NSCLC cell proliferation and metastasis by exosomal miR-454-3p.
CONCLUSIONS: Exosomal miR-454-3p enhanced the progression of NSCLC cells through HHEX. miR-454-3p may be a therapeutic target for NSCLC.

Keywords:  HHEX; NSCLC; Serum exosomes; malignant progression; miR-454-3p

DOI:  https://doi.org/10.1016/j.mcp.2025.102019
Int J Mol Sci. 2025 Feb 05. pii: 1345. [Epub ahead of print]26(3):

Roles, Functions, and Pathological Implications of Exosomes in the Central Nervous System.

Sonia Spinelli, Domenico Tripodi, Nicole Corti, Elena Zocchi, Maurizio Bruschi, Valerio Leoni, Roberto Dominici.

  Exosomes are a subset of extracellular vesicles (EVs) secreted by nearly all cell types and have emerged as a novel mechanism for intercellular communication within the central nervous system (CNS). These vesicles facilitate the transport of proteins, nucleic acids, lipids, and metabolites between neurons and glial cells, playing a pivotal role in CNS development and the maintenance of homeostasis. Current evidence indicates that exosomes from CNS cells may function as either inhibitors or enhancers in the onset and progression of neurological disorders. Furthermore, exosomes have been found to transport disease-related molecules across the blood-brain barrier, enabling their detection in peripheral blood. This distinctive property positions exosomes as promising diagnostic biomarkers for neurological conditions. Additionally, a growing body of research suggests that exosomes derived from mesenchymal stem cells exhibit reparative effects in the context of neurological disorders. This review provides a concise overview of the functions of exosomes in both physiological and pathological states, with particular emphasis on their emerging roles as potential diagnostic biomarkers and therapeutic agents in the treatment of neurological diseases.

Keywords:  blood–brain barrier; exosomes; extracellular vesicles (EVs); neurodegenerative diseases; peripheral–brain axis; therapeutic delivery

DOI:  https://doi.org/10.3390/ijms26031345
J Control Release. 2025 Feb 08. pii: S0168-3659(25)00115-4. [Epub ahead of print]380 330-347

Controlled delivery of HIF-1α via extracellular vesicles with collagen-binding activity for enhanced wound healing.

Sungmi Jeon, Seongeon Cho, Seongkyeong Yoo, Yeji Lee, Jiyoung Goo, Yu Jin Jeong, Gi-Hoon Nam, Hyun-Tae Shin, Jong-Wan Park, Cherlhyun Jeong, Sang Wha Kim, Iljin Kim, In-San Kim.

  Chronic wounds are often characterized by prolonged inflammation, impaired angiogenesis, and dysregulated hypoxic response, partly caused by the insufficient activation of hypoxia-inducible factor-1 alpha (HIF-1α). This study investigated the potential of engineered extracellular vesicles (EVs) to deliver a stable, constitutively active form of HIF-1α (scHIF-1α) to promote wound healing. A collagen-binding domain (CBD) was integrated into EVs to enhance their retention at wound sites, and collagen sponges were employed as scaffolds to ensure sustained, localized release of scHIF-1α EVs. In vitro studies have demonstrated that scHIF-1α EVs significantly improved cell proliferation, migration, and angiogenesis in dermal fibroblasts, endothelial cells, and keratinocytes-key cells involved in the wound healing process. In vivo, scHIF-1α EVs accelerated wound closure, enhanced tissue regeneration, and promoted angiogenesis in various wound healing models, including excisional wounds, surgical skin flaps, and diabetic wounds. The integration of CBD further enhanced EV retention, amplifying therapeutic outcomes. These results propose that scHIF-1α delivery via EVs, particularly when combined with collagen-based sustained-release systems, offers a promising and patient-friendly therapeutic strategy for treating chronic wounds.

Keywords:  Collagen-binding domain; Extracellular vesicles; HIF-1α; Sustained release; Tissue regeneration; Wound healing

DOI:  https://doi.org/10.1016/j.jconrel.2025.02.010
J Nanobiotechnology. 2025 Feb 12. 23(1): 107

Engineered extracellular vesicles with sequential cell recruitment and osteogenic functions to effectively promote senescent bone repair.

Lei Qi, Jing Wang, Jinge Yan, Weidong Jiang, Weiwen Ge, Xin Fang, Xudong Wang, Steve Gf Shen, Lu Liu, Lei Zhang.

  Senescent mandibular bone repair poses a formidable challenge without a completely satisfactory strategy. Endogenous cell recruitment and osteogenic differentiation are two sequential stages in bone regeneration, and disruptions in these two processes present significant obstacles to senescent bone repair. To address these issues, engineered extracellular vesicles (EV) with sequential stem cell recruitment and osteogenic functions were developed. This study demonstrated that Apt19s-engineered extracellular vesicles (Apt19s-EV) recognize and recruit bone marrow mesenchymal stem cells derived from old rats (O-BMSCs) specifically and effectively. MiR-376b-5p, identified by RNA sequencing and transfection, was significantly decreased in O-BMSCs, and it was selected to construct miR-376b-5p-engineered extracellular vesicles (376b-EV). 376b-EV could promote osteogenesis and alleviate senescence of O-BMSCs by targeting Camsap1. To combine the advantages of Apt19s and miR-376b-5p, dual engineered extracellular vesicles (Apt-376b-EV) comprising both Apt19s and miR-376b-5p modifications were constructed. To further validate its function, Gelatin methacryloyl (GelMA) hydrogel was used as a carrier to construct the Apt-376b-EV@GelMA delivery system. The in vitro results have demonstrated that Apt-376b-EV@GelMA could recruit O-BMSCs, alleviate senescence and promote osteogenic differentiation sequentially. Notably, the in vivo study also showed that Apt-376b-EV@GelMA could sequentially recruit endogenous stem cells and enhance new bone formation in senescent bone fracture and critical-sized defect models. In summary, the dual engineered extracellular vesicles, Apt-376b-EV, offer an appealing solution for recruiting endogenous stem cells and promoting bone repair sequentially in the senescent microenvironment, which may broaden the clinical applications of engineered EV and provide valuable strategies for treating senescent bone-related diseases in the future clinical work.

Keywords:  Cell recruitment; Engineered extracellular vesicles; Osteogenesis; Senescent bone repair

DOI:  https://doi.org/10.1186/s12951-025-03168-6
Biomaterials. 2025 Feb 04. pii: S0142-9612(25)00084-5. [Epub ahead of print]318 123165

Glycoengineered stem cell-derived extracellular vesicles for targeted therapy of acute kidney injury.

So Hee Kim, Chan Ho Kim, Chang Hyun Lee, Jungmi Lee, Heegun Kang, Sohyun Cho, Won Ho Jang, Minsung Park, Minji Ha, Jiyeon Kim, Wooram Um, Seunglee Kwon, Sangho Lee, Jin Woong Kim, Chan-Hwa Chung, Jae Hyung Park.

  Acute kidney injury (AKI) is associated with high morbidity and mortality rates, primarily due to the lack of effective therapeutic options for kidney repair. To restore the biological function of injured kidney, there is a need to protect renal tubular epithelial cells (RTECs) and regulate M1 macrophages, responsible for progress of AKI. Herein, based on metabolic glycoengineering-mediated click chemistry, we prepare the engineered extracellular vesicles (pSEVs), derived from PEGylated hyaluronic acid (HA)-modified mesenchymal stem cells. Owing to their cell-protective and anti-inflammatory properties, pSEVs effectively prevent the apoptosis of RTECs and inhibit the polarization of macrophages into an inflammatory phenotype in vitro. When systemically administered into the cisplatin-induced AKI animal model, pSEVs selectively accumulate in injured kidneys via HA-mediated binding to CD44 and toll-like receptor4 which are over-expressed on RTECs and M1 macrophages, respectively. This targeted delivery efficiently alleviates AKI-related symptoms, as evidenced by delayed kidney weight reduction, and decreased levels of creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin. Overall, pSEVs show potent anti-inflammatory effects and specific targeting to injured kidneys, presenting a considerable potential as the therapeutics for AKI.

Keywords:  Acute kidney injury; Extracellular vesicle; Mesenchymal stem cell; Metabolic glycoengineering; Regenerative medicine

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123165