bims-engexo 2025-04-20 papers

Fundam Res. 2025 Mar;5(2): 851-867

Engineering exosomes and exosome-like nanovesicles for improving tissue targeting and retention.

Lanya Li, Fei Wang, Dashuai Zhu, Shiqi Hu, Ke Cheng, Zhenhua Li.

Exosomes are natural nano-size particles secreted by human cells, containing numerous bioactive cargos. Serving as crucial mediators of intercellular communication, exosomes are involved in many physiological and pathological processes, such as inflammation, tissue injury, cardiovascular diseases, tumorigenesis and tumor development. Exosomes have exhibited promising results in the diagnosis and treatment of cancer, cardiovascular diseases and others. They are a rapidly growing class of drug delivery vehicles with many advantages over conventional synthetic carriers. Exosomes used in therapeutic applications encounter several challenges, such as the lack of tissue targeting capabilities and short residence time. In this review, we discuss recent advances in exosome engineering to improve tissue targeting and describe the current types of engineered exosome-like nanovesicles, and summarize their preclinical applications in the treatment of diseases. Further, we also highlight the latest engineering strategies developed to extend exosomes retention time in vivo and exosome-like nanovesicles.

Keywords: Engineering; Exosome-like nanovesicles; Exosomes; Retention; Targeting

DOI: https://doi.org/10.1016/j.fmre.2024.03.025

Mater Today Bio. 2025 Jun;32 101648

Harnessing engineered exosomes as METTL3 carriers: Enhancing osteogenesis and suppressing lipogenesis in bone marrow mesenchymal stem cells for postmenopausal osteoporosis treatment.

Tao Li, Jiangminghao Zhao, Jinghong Yuan, Rui Ding, Guoyu Yang, Jian Cao, Xiaokun Zhao, Jiahao Liu, Yuan Liu, Peichuan Xu, Jianjian Deng, Xinxin Miao, Xigao Cheng.

Postmenopausal osteoporosis (PMOP), a prevalent skeletal disorder among women post-menopause, has emerged as a pressing global public health concern. Exosomes derived from serum have exhibited encouraging therapeutic potential in addressing PMOP, albeit with underlying mechanisms requiring deeper exploration. To elucidate these mechanisms, we devised a mouse model by surgically inducing ovariectomy and isolated exosomes from serum samples. Subsequently, we employed qRT-PCR, Western blotting, and immunofluorescence analysis to quantify relevant gene and protein expression patterns. To assess the biological effects on treated cells and tissues, we utilized ARS staining, oil red O staining, and micro-CT analysis. Additionally, we examined the METTL3/FOXO1 m6A site interaction and the FOXO1/YTHDF1 complex using dual-luciferase reporter assays and RIP assays. The m6A modification levels of FOXO1 were quantified via MeRIP-PCR. Furthermore, we engineered bone marrow mesenchymal stem cell exosomes by loading abundant METTL3 mRNA and decorating their surfaces with bone-targeting peptides. The successful synthesis and bone-targeting capabilities of these modified exosomes were validated through electron microscopy, in vivo imaging, and immunofluorescence staining. Our findings reveal that METTL3, in collaboration with YTHDF1 within serum-derived exosomes, enhances FOXO1 gene transcription by fostering m6A modification of FOXO1. This, in turn, promotes osteogenic differentiation of bone marrow mesenchymal stem cells while inhibiting lipogenic differentiation. Notably, our engineered exosomes, BT-oe-METTL3-EXO, not only harbor high levels of METTL3 but also demonstrate exceptional bone-targeting efficiency. In vitro studies demonstrated that BT-oe-METTL3-EXO significantly mitigated bone mass loss induced by ovariectomy in mice, bolstered osteogenic differentiation of mouse bone marrow mesenchymal stem cells, and inhibited lipogenic differentiation. Collectively, our research underscores the pivotal regulatory function of serum-derived exosomes in human bone marrow stem cells (hBMSCs) and underscores the promising therapeutic potential of BT-oe-METTL3-EXO for combating postmenopausal osteoporosis.

Keywords: Lipogenic differentiation; Osteogenic differentiation; Postmenopausal osteoporosis; Serum exosomes; m6A RNA modification

DOI: https://doi.org/10.1016/j.mtbio.2025.101648

J Orthop Surg Res. 2025 Apr 15. 20(1): 373

Quercetin-primed MSC exosomes synergistically attenuate osteoarthritis progression.

Mingfeng Lu, Aiju Lou, Junqing Gao, Shilin Li, Lilei He, Weifeng Fan, Lilian Zhao.

BACKGROUND: Osteoarthritis (OA), a degenerative joint disease characterized by cartilage degradation and inflammation, lacks effective disease-modifying therapies. Quercetin, a bioactive flavonoid derived from Traditional Chinese Medicine, exhibits anti-inflammatory and chondroprotective properties but is limited by poor bioavailability. Mesenchymal stem cell-derived exosomes (MSC-Exos) offer a promising strategy for targeted drug delivery and cartilage regeneration.
METHODS: Bone marrow-derived MSC exosomes (Que-Exo) were isolated after preconditioning with quercetin (1µM, 24 h). Their effects were evaluated in IL-1β-stimulated chondrocytes via RT-qPCR, Western blot, transcriptomics, and proteomics. An ACLT-induced OA mouse model received intra-articular injections of Que-Exo, with cartilage integrity assessed by Safranin O staining and OARSI scoring.
RESULTS: Que-Exo significantly reduced IL-1β-induced pro-inflammatory markers (MMP9 and COX-2) and restored cartilage repair genes (SOX9 and Collagen II) compared to untreated exosomes. Multi-omics analyses revealed activation of PI3K-AKT signaling and glutathione metabolism pathways. In vivo, Que-Exo mitigated cartilage degradation and preserved proteoglycan content.
CONCLUSIONS: Quercetin-preconditioned MSC exosomes synergistically enhance chondroprotection and anti-inflammatory effects, offering a novel therapeutic strategy for OA by combining herbal bioactive compounds with exosome-mediated delivery.

Keywords: Chondroprotection; Engineered exosomes; Multi-omics analysis; Osteoarthritis; Quercetin

DOI: https://doi.org/10.1186/s13018-025-05785-1

Bioact Mater. 2025 Aug;50 95-115

An engineered M2 macrophage-derived exosomes-loaded electrospun biomimetic periosteum promotes cell recruitment, immunoregulation, and angiogenesis in bone regeneration.

Zhuohao Wen, Shuyi Li, Yi Liu, Xueyan Liu, Huiguo Qiu, Yuejuan Che, Liming Bian, Miao Zhou.

The periosteum, a fibrous tissue membrane covering bone surfaces, is critical to osteogenesis and angiogenesis in bone reconstruction. Artificial periostea have been widely developed for bone defect repair, but most of these are lacking of periosteal bioactivity. Herein, a biomimetic periosteum (termed PEC-Apt-NP-Exo) is prepared based on an electrospun membrane combined with engineered exosomes (Exos). The electrospun membrane is fabricated using poly(ε-caprolactone) (core)-periosteal decellularized extracellular matrix (shell) fibers via coaxial electrospinning, to mimic the fibrous structure, mechanical property, and tissue microenvironment of natural periosteum. The engineered Exos derived from M2 macrophages are functionalized by surface modification of bone marrow mesenchymal stem cell (BMSC)-specific aptamers to further enhance cell recruitment, immunoregulation, and angiogenesis in bone healing. The engineered Exos are covalently bonded to the electrospun membrane, to achieve rich loading and long-term effects of Exos. In vitro experiments demonstrate that the biomimetic periosteum promotes BMSC migration and osteogenic differentiation via Rap1/PI3K/AKT signaling pathway, and enhances vascular endothelial growth factor secretion from BMSCs to facilitate angiogenesis. In vivo studies reveal that the biomimetic periosteum promotes new bone formation in large bone defect repair by inducing M2 macrophage polarization, endogenous BMSC recruitment, osteogenic differentiation, and vascularization. This research provides valuable insights into the development of a multifunctional biomimetic periosteum for bone regeneration.

Keywords: Biomimetic periosteum; Bone regeneration; Engineered exosome; Immune regulation; Osteogenic induction

DOI: https://doi.org/10.1016/j.bioactmat.2025.03.027