bims-engexo 2025-07-06 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–07–06
seven papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered Exosome-Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia.
Engineered Exosomes Delivering bta-miR-223 Alleviate Staphylococcus aureus-Induced Mastitis in Mice via the TLR4/NF-κB Signaling Pathway.
Engineered Foxp1high Exosomes Ameliorates Systemic Lupus Erythematosus.
Human placental mesenchymal stem cell-derived exosomes carrying hsa-let-7i-5p mitigate lung injury in a murine model of aspiration pneumonia.
Engineered NIR-Responsive Exosomes for Synergistic Photoimmunotherapy of Hepatocellular Carcinoma.
Exosomal Noncoding RNAs in Renal Cell Carcinoma: Mechanisms, Roles, and Therapeutic Potential.
Decoding the Tumor Microenvironment: Exosome-Mediated Macrophage Polarization and Therapeutic Frontiers.

Exploration (Beijing). 2025 Jun;5(3): 20240349

Engineered Exosome-Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia.

Jialei Yang, Shipo Wu, Miao He.

  Stroke remains the leading cause of neurological mortality and disability worldwide, with post-stroke inflammation significantly hindering neural repair. Despite its critical impact, mechanism-based therapeutic strategies are scarce. In this study, we uncovered a critically important yet previously unexamined cell population, p21+CD86+ microglia, which accumulated in ischemic region. Unexpectedly, we discovered that p21 interacted with C/EBPβ, driving C/EBPβ-dependent transcription and upregulating key pro-inflammatory factors such as Il6, Il1β, Cxcl2, and Cxcl10. To specifically target and eliminate these pathogenic p21+CD86+ microglia, we engineered exosomes with a peptide that selectively binds CD86+ microglia and loaded them with the senolytic Quercetin. Furthermore, we developed an optimized, stable Que@micro-Exo therapeutic formulation. Systemic administration of Que@micro-Exo robustly reduced p21+CD86+ microglia and suppressed their pro-inflammatory phenotype. Notably, functional analyses revealed that Que@micro-Exo treatment mitigated blood-brain barrier disruption, promoted beneficial microglial polarization, decreased neutrophil infiltration, and significantly enhanced functional recovery following cerebral ischemia, all with a favorable safety profile. Our preclinical findings lay the foundation for targeting p21+CD86+ microglia as a novel therapeutic strategy, highlighting the potential of exosome-based senolytic anti-inflammatory therapy for stroke and other central nervous system disorders.

Keywords:  engineered exosomes; extracellular vesicles; ischemic stroke; microglia; senescence; targeted delivery

DOI:  https://doi.org/10.1002/EXP.20240349
J Agric Food Chem. 2025 Jul 03.

Engineered Exosomes Delivering bta-miR-223 Alleviate Staphylococcus aureus-Induced Mastitis in Mice via the TLR4/NF-κB Signaling Pathway.

Yuxuan Wang, Kun Ouyang, Ying Nie, Jingshuo Yang, Yunxin Liao, Xingping Chen, Hailong Wang, Junyi Luo, Jiajie Sun, Qianyun Xi, Binglei Shen, Ting Chen, Yongliang Zhang.

  Bovine mastitis is an inflammatory disease of the mammary gland, frequently associated with infection by Staphylococcus aureus. Effective delivery of the antiinflammatory microRNA bta-miR-223 remains a challenge. In this study, we constructed engineered exosomes loaded with bta-miR-223 and demonstrated their antiinflammatory effects both in vitro (Mac-T cells) and in vivo (mice). Overexpression of bta-miR-223 reduced the expression of IL-6 and IL-1β in a lipoteichoic acid-induced Mac-T cell inflammation model. Following tail vein injection in lactating mice, the engineered exosomes accumulated in the mammary gland, alleviated S. aureus-induced inflammation, and increased the expression of barrier-related proteins ZO-1, claudin-1, and occludin. Mechanistically, bta-miR-223 inhibited RHOB expression and modulated the TLR4/NF-κB pathway. These results demonstrate that exosome-mediated delivery of bta-miR-223 effectively alleviates mammary inflammation, providing a novel strategy for nucleic acid nanotherapy.

Keywords:  Staphylococcus aureus; bovine mastitis; bta-miR-223; engineered exosomes; nanotherapeutics

DOI:  https://doi.org/10.1021/acs.jafc.5c04371
Adv Sci (Weinh). 2025 Jul 03. e15712

Engineered Foxp1high Exosomes Ameliorates Systemic Lupus Erythematosus.

Luhan Niu, Qianmin Ou, Qianhui Ren, Zhengshi Li, Hongcheng Chen, Fangcao Lei, Xueli Mao, Songtao Shi, Zetao Chen, Wei Teng.

  Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and impaired Treg cell differentiation. Mesenchymal stem cell-derived exosomes (MSC-exos) hold promise for treating immune-related diseases, while their clinical application is hindered by the limited production and non-specific organ distribution. In this study, a combined engineering strategy is developed for MSC-exo via aggregation culture and genetic editing, achieving a substantial increase in both exosome yield and therapeutic specificity in SLE. First, MSCs produce a high yield of engineered exosomes through an aggregation culture engineering strategy (Agg-exo), demonstrating immune organ targeting and promoting Tregs via the Foxp1/STAT5/Foxp3 axis. Then, MSCs are engineered by overexpressing Foxp1 in order to acquire Foxp1high Agg-exo with enhanced immunomodulatory properties, which showes superior therapeutic effect for SLE. Taken together, a newly dual-engineering strategy is developed to produce high-yield, Foxp1high Agg-exo, which solved the limitation of low-yield production and non-specific organ distribution of MSC-exos. This innovative strategy holds great potential for the development of exosome-based therapies in autoimmune diseases.

Keywords:  aggregation; exosome engineering; foxp1; regulatory T cells; systemic lupus erythematosus

DOI:  https://doi.org/10.1002/advs.202415712
Korean J Anesthesiol. 2025 Jul 01.

Human placental mesenchymal stem cell-derived exosomes carrying hsa-let-7i-5p mitigate lung injury in a murine model of aspiration pneumonia.

Ching-Wei Chuang, Hong-Phuc Nguyen Vo, Yen-Hua Huang, I-Lin Tsai, Chao-Yuan Chang, Chun-Jen Huang.

   Background: Aspiration pneumonia (AP), which can be caused by gastric content inhalation into the lower airways, causes acute lung injury (ALI) through complex mechanisms, including inflammation, oxidative stress, and apoptosis. Here, we evaluated the efficacy of exosomes derived from human placental mesenchymal stem cells (hpMSCs) in mitigating ALI in a murine model of AP. We also investigated the role of hsa-let-7i-5p, the most abundant miRNA in hpMSC-derived exosomes, in this respect.
Methods: Adult male C57BL/6 mouse AP models were administered hpMSC-derived exosomes (APExo group) or phosphate-buffered saline (AP group) intra-tracheally. After 48 h, the mice were euthanized and evaluated. The effects of hsa-let-7i-5p were assessed by specific inhibition or overexpression.
Results: Compared with the APExo group, the AP group exhibited significantly greater ALI, as evidenced by histological damage, increased lung injury scores, impaired lung function, increased leukocyte infiltration, and elevated tissue edema (all P < 0.05). The untreated AP group also showed more inflammation, characterized by nuclear factor-κB upregulation, macrophage M1 polarization, and cytokine level elevation (tumor necrosis factor-α, interleukin-1β, and interleukin-6), as well as increased oxidation and activation of the apoptosis pathway (all P < 0.05). Notably, the therapeutic effects of hpMSC-derived exosomes were compromised by specific inhibition of hsa-let-7i-5p. Furthermore, engineered exosomes derived from genetically modified RAW264.7 overexpressing hsa-let-7i-5p demonstrated therapeutic effects against AP similar to those obtained with hpMSC-derived exosomes.
Conclusions: In a murine AP model, intra-tracheal administration of hpMSC-derived exosomes has ALI-mitigating effects, involving inflammation, oxidation, and apoptosis modulation, with hsa-let-7i-5p playing a pivotal mediating role.

Keywords:  Aspiration pneumonia; Exosomes; Hsa-let-7i microRNA; Lung injury; Mesenchymal stem cells; Mice

DOI:  https://doi.org/10.4097/kja.25037
ACS Omega. 2025 Jun 24. 10(24): 25675-25685

Engineered NIR-Responsive Exosomes for Synergistic Photoimmunotherapy of Hepatocellular Carcinoma.

Youbo Zhao, Yanan Li, Zhiwei He, Menghuan Li, Di Zhao, Chao Yu.

T-cell immunotherapy holds tremendous promise for treating various types of cancer by boosting the infiltration and activity of T cells within tumor tissues. However, efficient recruitment of peripheral T cells to the tumor microenvironment (TME) remains a major clinical challenge. To address this limitation, here, we report an exosomal (EXO) immunotherapy for remodeling the immunosuppressive TME of hepatocellular carcinoma (HCC) into an immunosupportive state in a remotely controllable manner, for which the HCC-secreted exosomes are engineered with CXCL9 chemokine and cypate photothermal transducers (cypate@EXO-CXCL9). The engineered exosomes could efficiently home to the HCC site through homotypic targeting. Upon exposure to near-infrared light, the cypate-mediated photothermal effect readily induces immunogenic death of tumor cells while simultaneously disrupting the exosomes to release CXCL9. The released CXCL9 effectively attracts T cells to the tumor site and is subsequently activated by the HCC-derived antigens and damage associated molecular patterns to mount robust antitumor immunity. This study provides a facile strategy for the remodeling of the immunosuppressive HCC microenvironment, offering an approach for improving immunotherapeutic efficacy of solid tumors in the clinic.

DOI: https://doi.org/10.1021/acsomega.5c01396
Crit Rev Oncol Hematol. 2025 Jul 02. pii: S1040-8428(25)00217-3. [Epub ahead of print] 104829

Exosomal Noncoding RNAs in Renal Cell Carcinoma: Mechanisms, Roles, and Therapeutic Potential.

Jiaming Zhu, Ye Ding, Qiaoping Xu.

  Exosomes, critical mediators within the tumor microenvironment (TME), facilitate intercellular communication by transferring bioactive molecules, including noncoding RNAs (ncRNAs). These extracellular vesicles, secreted by nearly all cell types and detectable in bodily fluids, selectively encapsulate functional ncRNAs, which play pivotal roles in tumorigenesis, progression, and therapeutic resistance. In renal cell carcinoma (RCC), exosomal ncRNAs have emerged as key regulators driving tumor proliferation, metastasis, and immunosuppression through mechanisms such as activation of the MAPK pathway, promotion of epithelial-mesenchymal transition (EMT), and modulation of immune cell polarization. Notably, exosomal ncRNAs contribute to drug resistance by mediating cross-talk between cancer cells and stromal components, including fibroblasts and tumor-associated macrophages (TAMs). Their inherent stability, conferred by protective lipid bilayers, enhances their potential as non-invasive diagnostic and prognostic biomarkers. Specific ncRNAs, such as miR-210 and circSDHC, exhibit differential expression in RCC patient sera and urine, offering high diagnostic accuracy for early detection and metastasis monitoring. Furthermore, targeting exosomal ncRNA biogenesis or their downstream pathways-via engineered exosomes loaded with therapeutic RNAs or inhibitors-represents a promising strategy to overcome resistance and improve treatment efficacy. This review comprehensively delineates the mechanistic roles of exosomal ncRNAs in RCC pathogenesis, highlights their clinical utility as biomarkers, and explores innovative therapeutic approaches to disrupt ncRNA-mediated oncogenic signaling. Advancing our understanding of exosome-ncRNA dynamics may unlock novel precision therapies for RCC, addressing unmet challenges in current clinical management.

Keywords:  Biomarkers; Exosome; Progression; Renal cell carcinoma; ncRNA

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104829
Int J Biol Sci. 2025 ;21(9): 4187-4214

Decoding the Tumor Microenvironment: Exosome-Mediated Macrophage Polarization and Therapeutic Frontiers.

Yilin Li, Jiaqi You, Zifang Zou, Guanghao Sun, Yuqing Shi, Yanbin Sun, Shun Xu, Xin Zhang.

The tumor microenvironment (TME) is dynamically shaped by interactions between tumor cells, immune cells, and stromal components. Among these, tumor-associated macrophages (TAMs) play dual roles in tumor progression. Exosomes are key mediators of intercellular communication and are crucial for modulating macrophage polarization. This review systematically summarizes the role of HIF-1α as the central regulator of tumor-derived exosomes under hypoxic conditions. Under endoplasmic reticulum stress (ERS), the STAT3 and PI3K/AKT/mTOR pathways activation is mediated by the inactivation of the Hsp90/Hippo pathway, which induces the expression of LncRNA HMMR-AS1 and specific miRNAs (e.g., miR-1246, let-7a, miR-301a-3p, etc.). Furthermore, the IRE1/PERK pathway regulates exosome secretion by carrying miR-23a-3p and miR-27a-3p or directly delivering PD-L1 protein, thus activating the PI3K/AKT pathway, inhibiting PTEN, and upregulating PD-L1 expression as well as increasing the M2 polarization of macrophages. This study also summarized the important matrices of exosomes' involvement in the interaction between tumor cells and macrophages in different systemic malignant tumors. Moreover, the bidirectional crosstalk between TAM-derived exosomes and other TME components (e.g., CD8+ T cells, fibroblasts) was also evaluated, which indicated their roles in immune evasion and metastasis. Further, engineering strategies, such as receptor-targeted exosomes and short palindromic repeats interference (CRISPRi)-based transcriptional silencing, were also discussed as emerging tools to enhance exosome specificity and therapeutic efficacy. This study proposes a roadmap for translating engineered exosomes into clinical immunotherapy regimens by integrating recent advances in spatial omics and artificial intelligence, and also addresses challenges in exosome isolation, stability, and biosafety.

DOI: https://doi.org/10.7150/ijbs.114222