bims-engexo 2025-05-18 papers

Zhonghua Zhong Liu Za Zhi. 2025 May 23. 47(5): 385-394

[Targeted therapy for colorectal cancer through miR-204-5p delivered by nanobody-engineered exosomes: an experimental study].

L Gong, L Tian, Y C Li, Z M Wu, Z H Huang.

Objective: To develop an EGFR-targeting nanobody engineered exosome drug delivery system and evaluate its antitumor efficacy for colorectal cancer. Methods: The HEK293T cell line stably expressing the pan-cancer inhibitor miR-204-5p, previously established by our group, was selected as a tool cell line to prepare miR-204-5p-enriched exosomes. Using metabolic glycoengineering combined with bioorthogonal reaction strategy, these exosomes were modified with the EGFR-specific nanobody 7D12. Western blot, electron microscopy, and dynamic light scattering were used to characterize the engineered exosomes. The tumor target potential of engineered exosomes was evaluated using immunofluorescence and RT-qPCR. The in vitro anti-tumor activities of engineered exosomes were evaluated using cell growth curves, colony formation, Transwell, and apoptosis analyses. The in vivo anti-tumor activity and safety of engineered exosomes were evaluated using a nude mouse xenograft tumor model. Results: The particle size of 7D12-hExo was (116.8±36.8) nm, with a potential of around -10 mV, and there was no significant change compared with the unmodified hExo. Immunofluorescence assay showed that the fluorescence intensity of the hExo group, 7D12-hExo group, and 7D12+7D12-hExo group were 48.4±3.9, 141.0±6.6, and 38.7±3.2 in EGFR+ HCT116 cells, respectively. Compared with the hExo group, the fluorescence intensity of HCT116 cells in the 7D12-hExo group was significantly enhanced (P＜0.05). Compared with the 7D12-hExo group, the fluorescence intensity in HCT116 cells in the 7D12+7D12-hExo group was significantly decreased (P＜0.05). However, there was no significant difference in the uptake of hExo and 7D12-hExo in EGFR- SW620 colorectal cancer cells. The number of cell clones, invasion, and migration of HCT116 cells in the hExo (204) group was 215.0±14.0, 862.3±61.4, and 1 197.0 ± 36.7, respectively, with an apoptosis rate of (14.1±1.4)%. The number of cell clones, invasion, and migration of HCT116 cells in the 7D12-hExo (204) group was (65.0±15.1), (232.0±27.9), (725.7±32.7), respectively, with an apoptosis rate of (29.3±1.0)%. The 7D12-hExo (204) significantly inhibited the proliferation, invasion, and migration ability of HCT116 cells (P＜0.05), resulting in promoting the apoptosis of HCT116 cells (P＜0.05). Nude mouse experiments showed that 7D12-hExo (204) significantly inhibited the growth of tumors transplanted with HCT116 cells, with the inhibition rate being 82.8%. However, there was no significant change in mouse weight, and H&E staining of major organs such as heart, liver, spleen, lung, and kidney did not show any abnormalities. Conclusion: Naturally miR-204-5p-loaded exosomes were successfully modified with nanobody 7D12, which can efficiently deliver miR-204-5p into EGFR+ tumor cells, thereby exerting good anti-tumor therapeutic effects.

DOI: https://doi.org/10.3760/cma.j.cn112152-20231024-00211

Biomaterials. 2025 May 08. pii: S0142-9612(25)00322-9. [Epub ahead of print]322 123403

Multi-targeted engineered hybrid exosomes as Aβ nanoscavengers and inflammatory modulators for multi-pathway intervention in Alzheimer's disease.

Bin Du, Qingqing Zou, Xin Wang, Hongqiang Wang, Xiaohai Yang, Qing Wang, Kemin Wang.

The pathogenesis of Alzheimer's disease (AD) was complex, including excessive deposition of β-amyloid (Aβ), microglia dysfunction, and neuroinflammation. Therefore, single-pathway treatment was not sufficient to ameliorate the multifaceted pathological changes associated with AD. Moreover, the low permeability of blood-brain barrier (BBB) and the lack of AD locus selectivity further limited the intervention efficacy of current AD drugs. In this study, a novel nanoparticle coating was designed by hybridizing the membrane from brain microvascular endothelial cell exosomes and macrophage exosomes, and combining polydopamine nanoparticles, resveratrol and Aβ-targeting aptamers to construct engineered exosomes (RPDA@Rb-A) with multiple targeting capabilities to intervene in Aβ clearance and regulate microglial dysfunction. Based on the homing effect of brain microvascular endothelial cell exosomes and the natural inflammation targeting ability of macrophage exosomes, RPDA@Rb-A can easily penetrate the blood brain barrier and accumulate in the brain inflammation site after capturing Aβ aggregates. RPDA@Rb-A can effectively intervene in AD through multi-pathway, including degraded toxic Aβ aggregates through local heating induced by near-infrared laser irradiation and alleviated neurotoxicity, promoted microglial clearance of Aβ by capturing Aβ, and modulated microglia-induced neuroinflammation by efficient delivery of small molecule drugs. In AD mouse model, the administration of RPDA@Rb-A resulted in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. The engineered exosomes based on membrane hybridization overcome the shortcomings of traditional drug carriers in poor penetration and insufficient targeting to the central nervous system, and provide a potential platform for multi pathways intervention in AD.

Keywords: Alzheimer's disease; Blood-brain barrier; Engineered exosomes; Multi-pathway intervention; Multi-targeted

DOI: https://doi.org/10.1016/j.biomaterials.2025.123403

Int J Nanomedicine. 2025 ;20 5873-5891

Intranasal Delivery of BACE1 siRNA and Berberine via Engineered Stem Cell Exosomes for the Treatment of Alzheimer's Disease.

Chunbin Sun, Shuang Sha, Yubang Shan, Xiaoyu Gao, Liang Li, Cencan Xing, Zhongbao Guo, Hongwu Du.

Introduction: Alzheimer's disease (AD) is a common progressive and irreversible neurodegenerative disease. AD accounts for 60%-70% of all dementia cases, ranking as the seventh leading cause of death globally. Human umbilical cord mesenchymal stem cells (hUC-MSCs) characterized by their abundant availability and low immunogenicity, have demonstrated significant therapeutic potential for AD in both preclinical studies and clinical trials. The use of exosomes can help mitigate the issues associated with cellular therapies. However, the clinical application of hUC-MSCs remains challenging due to their inability to effectively traverse the blood-brain barrier (BBB) and reach pathological sites. Therapeutic strategies utilizing exosomes derived from hUC-MSCs (Exos) have emerged as an effective approach for AD intervention.
Methods: Here, we used ultrasound to construct multifunctional Exos (MsEVB@R/siRNA) for AD therapy. We obtained small interfering RNA for β-site precursor protein lyase-1 (BACE1 siRNA) and berberine for co-delivery into the brain. Berberine, a classical anti-inflammatory agent, effectively alleviates neuroinflammation in AD pathogenesis. BACE1 serves as the pivotal cleavage enzyme in amyloid β-protein (Aβ) formation, where silencing BACE1 synthesis through BACE1 siRNA significantly reduces Aβ production. In a 5xFAD mouse model, Exos selectively targeted microglial and neuronal cells after nasal delivery under the action of neural cell-targeting peptide rabies virus glycoprotein 29 (RVG29).
Results: BACE1 siRNA and berberine (BBR) loading enhanced the effectiveness of Exos in improving cognitive function, promoting nerve repair and regeneration, reducing inflammatory cytokine expression, and suppressing glial responses. BACE1 siRNA release was confirmed to reduce BACE1 expression and Aβ deposition. Concurrently, berberine effectively suppressed the release of inflammatory factors, thereby reducing neuroinflammation.
Conclusion: In conclusion, the nasal delivery of engineered exosomes is a potentially effective method for treating AD.

Keywords: Alzheimer’s disease; engineering exosomes; intranasal delivery

DOI: https://doi.org/10.2147/IJN.S506793

Mol Neurobiol. 2025 May 10.

Roles for Exosomes from Various Cellular Sources in Spinal Cord Injury.

Wangnan Mao, Xinghao Liu, Chen Chen, Tongfu Luo, Zheng Yan, Lianguo Wu, Zhongcheng An.

Spinal cord injury (SCI) is a severe disorder characterized by regeneration challenges in the central nervous system (CNS), resulting in permanent paralysis, loss of sensation, and abnormal autonomic functions. The complex pathophysiology of SCI poses challenges to traditional treatments, highlighting the urgent need for novel treatment approaches. Exosomes have emerged as promising candidates for SCI therapy because of their ability to deliver a wide range of bioactive molecules, such as RNAs, proteins, and lipids, to target cells with minimal immunogenicity, which contribute to anti-inflammatory, anti-apoptotic, autophagic, angiogenic, neurogenic, and axon remodeling activities. In this study, we classified exosomes from different sources into four categories based on the characteristics of the donor cells (mesenchymal stem cells, neurogenic cells, immune cells, vascular-associated cells) and provided a detailed summary and discussion of the current research progress and future directions for each source. We also conducted an in-depth investigation into the applications of engineered exosomes in SCI therapy, focusing on their roles in drug delivery and combination with surface engineering technologies and tissue engineering strategies. Finally, the challenges and prospects of exosomal clinical applications in SCI repair are described.

Keywords: Cellular sources; Exosomes; Spinal cord injury; Therapeutics

DOI: https://doi.org/10.1007/s12035-025-05040-y