bims-engexo 2025-12-14 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–12–14
eight papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

iRGD-engineered exosomes mediate siMYC delivery for effective tumor suppression in triple-negative breast cancer.
Targeted delivery of Prussian blue modified exosomes to CD90-expressing synovial fibroblasts for Rheumatoid arthritis immunotherapy.
A single extracellular vesicle-based platform supporting both RBD protein and mRNA vaccination against SARS-CoV-2.
CAR Therapies: Ex Vivo and In Vivo Potential of Exosomes and Biomimetic Nanoparticles.
Targeting pre-metastatic niche with inhalable dendritic cell vesicles to prevent breast cancer lung metastasis.
Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer's disease: Modulating oxidative stress and neuroinflammation.
Optimizing Exosome Lipid Hybrid Nanoparticles for Enhanced siRNA Delivery and Improved Therapeutic Anticancer Efficacy In Vivo.
High-Yield Outer Membrane Vesicles Derived From Probiotics as a Nanoplatform for Precise Treatment and Prophylaxis of Pseudomonas aeruginosa Infection.

Nanoscale. 2025 Dec 12.

iRGD-engineered exosomes mediate siMYC delivery for effective tumor suppression in triple-negative breast cancer.

Hui Li, Weiguang Yuan, Jialin Liu, Yingjie Wang, Fang Fang, Yuanyuan Yu, Jianxun Hou, Mengru Jin, Siwei Li, Siyu Liu, Yajie Gong, Yijun Chu, Xingda Zhang, Shilu Zhao, Wenhui Hao, Xuquan Qin, Qinchen Fan, Xi Chen, Youxue Zhang, Da Pang, Xianyu Zhang.

Triple-negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis. MYC overexpression drives tumor progression, but the lack of an efficient siMYC delivery system remains a major challenge. Exosomes (Exos), as biocompatible nanocarriers, offer a solution. Here, we engineered internalizing RGD peptide (iRGD)-Exos to enhance siMYC delivery and improve therapeutic efficacy. iRGD-Exos were generated by transfecting FreeStyle™ 293-F (293-F) cells with an iRGD-Flag-Lamp2b plasmid, followed by ultracentrifugation and isolation. siMYC was loaded via electroporation. Exosomes were characterized, and their uptake efficiency was measured. CCK-8 assays and flow cytometry were conducted to analyze the effects of exosomes on the proliferation and apoptosis of TNBC cells. Apoptosis staining was also conducted on patient-derived organoids (PDOs). In a TNBC xenograft mouse model, fluorescence imaging, tumor volume measurement, and histological analysis were conducted to assess tumor targeting and therapeutic effects of engineered exosomes. Systemic toxicity was evaluated based on hematological, biochemical, and histopathological analyses. The iRGD modification significantly enhanced the uptake efficiency of exosomes by αvβ3 integrin-positive Hs578T TNBC cells. Following siMYC loading via electroporation, iRGD-Exos-siMYC markedly suppressed the proliferation of TNBC cells and induced their apoptosis. Additionally, it promoted apoptosis in PDOs, further supporting its antitumor potential. In vivo, iRGD-Exos-siMYC exhibited superior tumor-targeting capability, effectively inhibiting tumor growth and significantly downregulating MYC expression. Moreover, biosafety evaluations confirmed that iRGD-Exos-siMYC possesses good biosafety. This study demonstrated that iRGD-modified exosomes can effectively deliver siMYC to TNBC cells, enhancing gene silencing and antitumor efficacy. The targeted exosomal drug delivery system showed high tumor selectivity and minimal systemic toxicity. These findings provide new insights into exosome-based gene therapy and highlight the value of iRGD-Exos-siMYC as a novel treatment strategy for TNBC.

DOI: https://doi.org/10.1039/d5nr04841a
Mater Today Bio. 2025 Dec;35 102580

Targeted delivery of Prussian blue modified exosomes to CD90-expressing synovial fibroblasts for Rheumatoid arthritis immunotherapy.

Hongkai Yang, Xinran Hu, Fu Zhu, Baofeng Zhao, Yixuan Wang, Yu Deng, Feng Jin, Yijia Zhang, Sen Lin, Xifan Mei.

  Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and joint destruction. Current therapeutic approaches face challenges such as systemic toxicity and insufficient targeting. Exosomes have emerged as novel carriers for RA treatment due to their inherent targeting capability, low immunogenicity, and efficient delivery capacity. This study aimed to construct a targeted delivery system (CD90-exo@PB) based on CD90-modified exosomes (CD90-exo) loaded with Prussian blue nanoparticles (PB) for specific therapy of RA. In vitro experiments demonstrated that CD90-exo@PB could be efficiently internalized by activated synovial fibroblasts (aFLS), significantly inhibiting aFLS migration through reduction of pro-inflammatory cytokines. In a collagen-induced arthritis (CIA) mouse model, near-infrared fluorescence imaging revealed targeted accumulation of CD90-exo@PB in inflamed joints, accompanied by effective alleviation of joint swelling. Mechanistic studies indicated that the therapeutic efficacy was closely associated with downregulation of pro-inflammatory cytokines. The developed CD90-exo@PB system integrates active targeting with antioxidant synergistic effects, providing an innovative strategy for precision therapy of RA with significant clinical translation potential.

Keywords:  CD90 antibody; Exosomes; Prussian blue nanoparticles; Rheumatoid arthritis; Targeted delivery system

DOI:  https://doi.org/10.1016/j.mtbio.2025.102580
J Control Release. 2025 Dec 06. pii: S0168-3659(25)01129-0. [Epub ahead of print]390 114515

A single extracellular vesicle-based platform supporting both RBD protein and mRNA vaccination against SARS-CoV-2.

Jihwa Chung, Kyoung Hwa Kim, Shung Hyun An, DaeHo Bae, Hyo Kyeong Kim, Yujeong Choi, Jae Hwan Kim, Kihwan Kwon, Seok-Hyun Kim.

  The COVID-19 pandemic has underscored the urgent need for safe, effective, and flexible vaccine platforms. Here, we present a modular extracellular vesicle (EV)-based vaccine system engineered using Shock Wave Extracellular Vesicle Engineering Technology (SWEET)-an acoustic shock wave-based post-loading method that enables high-efficiency encapsulation of either protein or mRNA antigens into immunostimulatory EVs. Using SARS-CoV-2 receptor-binding domain (RBD) as a model antigen, we achieved robust encapsulation of RBD protein (∼69 %, relative to the initial input amount) and RBD mRNA (∼75 %, representing the Benzonase-protected fraction relative to total EV-associated mRNA) into EVs derived from LPS-activated THP-1 monocytes, without compromising vesicle integrity. Both protein- and mRNA-loaded EV vaccines elicited potent, adjuvant-free humoral and balanced Th1/Th2 cellular immune responses in mice, with neutralizing antibody titers and cytokine profiles comparable to or exceeding those of alum-adjuvanted controls. Notably, lyophilized EV vaccines retained immunogenicity after 7 days at 4 °C, supporting cold chain-independent distribution. To our knowledge, this is the first demonstration that a single post-loaded EV platform can independently deliver either functional protein or mRNA vaccines with quantifiable intracellular expression and robust immune activation. The SWEET platform's scalability, modularity, and compatibility with clinically familiar components position it as a promising next-generation vaccine and drug delivery technology.

Keywords:  Antigen delivery; Extracellular vesicles; Non-lipid nanoparticle (non-LNP) delivery; Post-loading encapsulation; Protein subunit vaccine; SARS-CoV-2; Shock wave extracellular vesicle engineering technology (SWEET); mRNA vaccine

DOI:  https://doi.org/10.1016/j.jconrel.2025.114515
Cancers (Basel). 2025 Nov 25. pii: 3766. [Epub ahead of print]17(23):

CAR Therapies: Ex Vivo and In Vivo Potential of Exosomes and Biomimetic Nanoparticles.

Ekaterina Tkachenko, Natalia Ponomareva, Konstantin Evmenov, Artyom Kachanov, Sergey Brezgin, Anastasiya Kostyusheva, Vladimir Chulanov, Elena Volchkova, Alexander Lukashev, Dmitry Kostyushev, Peter Timashev.

  Chimeric antigen receptor (CAR) therapy represents a promising modality for treating cancer and autoimmune diseases, employing genetically engineered immune cells. Despite remarkable clinical outcomes, its broad implementation is constrained by significant challenges, including toxicity, limited specificity, and complexities associated with genetic material delivery. Biological nanoparticles, such as exosomes, virus-like particles, and biomimetic nanostructures, possess unique properties that can address these limitations. These nanoplatforms enable targeted delivery of genetic constructs, mitigate the risk of cytokine release syndrome, modulate CAR cell activity, and can function as biosensors. Furthermore, they facilitate non-viral, in vivo CAR cell engineering, streamlining the process compared to conventional ex vivo methods. The advancement of in vivo strategies underscores the critical need to overcome toxicity hurdles inherent to current CAR-T platforms. In this context, exosomes and biomimetic nanoparticles offer considerable potential due to their innate biocompatibility, programmability, and versatile cargo capacity for payloads like mRNA and circular RNA. This review comprehensively outlines contemporary genetic platforms for CAR expression and examines the opportunities presented by biological delivery vehicles. It focuses on recent achievements and revisits fundamental CAR principles through the lens of emerging technologies aimed at confronting persistent challenges in the field.

Keywords:  CAR-T therapy; T cells; biological nanoparticles; gene therapy; targeted delivery

DOI:  https://doi.org/10.3390/cancers17233766
J Nanobiotechnology. 2025 Dec 12. 23(1): 765

Targeting pre-metastatic niche with inhalable dendritic cell vesicles to prevent breast cancer lung metastasis.

Qingqing Leng, Zhengxin Yu, Yu Zhao, Yue Shao, Qiuyang Jin, Qiyu Zhao, Ying Yang, Mengmeng Ji, Hua Yang, Lili Ren, Guang Jia, Xueyi Wang, Jinchao Zhang, Zhenhua Li, Huifang Liu.

  Distant metastasis remains the primary cause of mortality in breast cancer, yet therapeutic options to prevent or treat metastatic progression are still limited. Emerging evidence suggests that the formation of the pre-metastatic niche (PMN) serves as a pivotal step in the process of breast cancer metastasis. Lung tissue is the major site of breast cancer metastasis with elevated prostaglandin E2 (PGE2) levels, which fosters immunosuppression and promotes niche establishment. Although EP2 and EP4 receptor antagonists have shown promise in counteracting PGE2-driven immunosuppression, their clinical translation is hindered by poor selectivity and bioavailability. To address these limitations, we developed a nanotherapeutic platform using dendritic cell-derived nanovesicles (NVs) engineered with α-lactalbumin (α-LA) and loaded with the EP2 antagonist TG6-10-1 and the EP4 antagonist GW627368, termed L-TG/GW-NVs. L-TG/GW-NVs exploit the homing ability of DC-derived NVs and retain immune-stimulatory molecules, thereby preventing PMN formation by blocking PGE2 signaling and reactivating suppressed dendritic cells and cytotoxic T cells. This synergistic strategy markedly suppressed lung metastasis by disrupting niche formation, enhancing immune activation, and reversing T cell exhaustion. Collectively, our findings establish a novel framework for metastatic breast cancer therapy and provide valuable insights for future translational studies and combinational immunotherapies.

Keywords:  Dendritic cell dysfunction; Dendritic extracellular vesicle; Lung metastasis; Pre-metastatic niche; Prostaglandin E2 antagonists

DOI:  https://doi.org/10.1186/s12951-025-03842-9
Biomater Adv. 2025 Nov 23. pii: S2772-9508(25)00446-7. [Epub ahead of print]181 214619

Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer's disease: Modulating oxidative stress and neuroinflammation.

Jing Xu, Ziyan He, Yaoxin Pan, Bangming Cao, Guofang Chen.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy.

Keywords:  Alzheimer's disease; Baicalein; Exosomes; Nanotherapeutics; Neuroinflammation and oxidative stress

DOI:  https://doi.org/10.1016/j.bioadv.2025.214619
ACS Nano. 2025 Dec 11.

Optimizing Exosome Lipid Hybrid Nanoparticles for Enhanced siRNA Delivery and Improved Therapeutic Anticancer Efficacy In Vivo.

Hend Mohamed Abdel-Bar, Steven Tandiono, Revadee Liam-Or, Calvin C L Cheung, Osama W M Hassuneh, Qingyang Lyu, Yue Qin, Shunping Han, Nadia Rouatbi, Julie Tzu-Wen Wang, Adam A Walters, Khuloud T Al-Jamal.

  Exosome lipid hybrid nanoparticles (ELNs) have emerged as promising drug delivery vehicles, integrating the innate targeting capabilities of exosomes with efficient cytosolic delivery of lipid nanoparticles. However, despite growing interest, the development of ELNs for nucleic acid delivery remains a formidable challenge, compounded by diverse production methods and a lack of systematic approaches to optimize their formulation and performance. This study employed a Box-Behnken design and two fabrication methods: freeze-thaw and sonication, to optimize the formulation of ELNs derived from exosomes of five distinct cancer cells. Formulation criteria focused on maximizing the fusion efficiency while minimizing particle size. The impact of the fusion method on cellular association and gene silencing of promising therapeutic targets, CD24, CD44, and CD47, was evaluated. The optimized formulations were subsequently assessed for therapeutic efficacy in 4T1 and B16F10 tumor models. Through careful manipulation of formulation variables, we obtained optimal ELNs with fusion efficiencies exceeding 50% and particle sizes under 170 nm while preserving exosomal markers CD9, CD63, and CD81. Cellular association studies revealed that ELNs specifically targeted their parental cell line, achieving ∼2.5-fold higher siRNA association compared to LNPs. Furthermore, the optimized ELNs facilitated the delivery of therapeutic siRNAs, resulting in robust gene silencing and consequently improved the in vitro macrophage-mediated phagocytosis of treated cancer cells. In vivo studies using 4T1 and B16F10 tumor models highlighted the enhanced therapeutic potential of the optimized ELNs, as evidenced by significant tumor targeting and growth inhibition. These findings underscore the importance of systematic formulation and method optimization in advancing ELNs as effective nucleic acid delivery platforms for cancer therapy.

Keywords:  CD24; CD44; CD47; DoE; extracellular vesicles; lipid nanoparticles; triple negative breast cancer

DOI:  https://doi.org/10.1021/acsnano.5c16991
J Extracell Vesicles. 2025 Dec;14(12): e70194

High-Yield Outer Membrane Vesicles Derived From Probiotics as a Nanoplatform for Precise Treatment and Prophylaxis of Pseudomonas aeruginosa Infection.

Yadong Yang, Lei Xu, Yongdong Li, Yu Sun, Yanan Tang, Zhibo Xiao, Mengyuan Li, Yi Chen, Yao Wang, Xihui Shen.

  Bacterial outer membrane vesicles (OMVs) are emerging as promising platforms for drug delivery and immunotherapy. However, bacteria only secrete a small amount of OMVs during the growth process, which seriously restricts their large-scale application. Here, a series of high-yield OMVs mutants is developed based on probiotic Escherichia coli Nissle 1917 (EcN). The mutant strain (EcNΔtolRΔmlaE) with the highest OMVs yield reported so far is identified and characterized, and its OMVs yield is 180.8 times that of the wild-type strain. More importantly, a high-yield OMVs mutant (EcNΔtolAΔnlpI) that derived OMVs can significantly improve the secretion efficiency of exogenous proteins is screened and engineered for enhanced scalability and versatility. Leveraging this platform, the prepared TOB-PslG-mOMVs nanoantibiotics, co-delivering glycosyl hydrolase (PslG) and tobramycin (TOB), synergistically disrupt biofilms and demonstrate potent antibacterial effects against Pseudomonas aeruginosa. Additionally, the prepared FI-mOMVs nanovaccines displaying the OprF190-342-OprI21-83 antigenic epitope fusion protein (FI) of P. aeruginosa can effectively induce robust humoral immune and cellular immune responses and significantly enhance protection against bacterial infection. Therefore, the OMVs nanoplatform thus represents a transformative approach, opening new avenues for combating multi-drug-resistant bacteria through innovative nanoantibiotic and nanovaccine technologies.

Keywords:  Pseudomonas aeruginosa; immunotherapy; nanoplatform; outer membrane vesicles; synergistic antibacterial

DOI:  https://doi.org/10.1002/jev2.70194