bims-engexo 2026-03-22 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–03–22
eleven papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Emerging strategies in exosome engineering: From cellular preconditioning to hybridization for targeted therapeutics.
Scalable Production of Multi-Source Hybrid Biomimetic Exosomes Co-Loaded with Therapeutic Plasmids for Treatment of High-Altitude Pulmonary Edema.
Exosome-Loaded Engineered circBDNF Promotes Spinal Cord Injury Repair Through the PI3K/AKT/mTOR Signaling Axis.
Intradermal Delivery of Catalase via Extracellular Vesicles for Targeted Photoaging Therapy.
Potential Strategies for Bacterial Infection Control: Outer Membrane Vesicle Based Bacterial Vaccines.
Exosome-based vaccines in cancer immunotherapy: antitumor mechanisms, engineering strategies, and challenges.
An exosome-biomimetic photothermal nanocarrier for IGF2BP2 siRNA delivery and enhanced ferroptosis in head and neck squamous cell carcinoma.
Dual-targeted hybrid nanovesicles coordinated bone-muscle regeneration via regulating the DUSP4/p38 MAPK pathway to reverse osteosarcopenia.
Extracellular vesicles delivering TIMP-2 modulate MMP-1, MMP-2, and MMP-9 expression in human lung adenocarcinoma A549 cells.
Pharmacological Breakthroughs with Extracellular Vesicles-Based Nanomedicine: A Targeted Strategy to Cross the Blood-Brain Barrier in Alzheimer's Disease.
Milk exosomes delivery of KPT-330 alleviates gastrointestinal adverse reactions and provides effective anti-diffuse large B-cell lymphoma therapy.

Biochem Biophys Res Commun. 2026 Feb 26. pii: S0006-291X(26)00297-4. [Epub ahead of print]812 153533

Emerging strategies in exosome engineering: From cellular preconditioning to hybridization for targeted therapeutics.

Rafie Belali, Maryam Jafar Sameri.

  Exosomes are nanosized extracellular vesicles that originate from all cell types. They have a precious role in intercellular communication and therapeutic delivery. Exosomes are considered attractive candidates because of their innate biocompatibility, low immunogenicity, and ability to transport bioactive molecules across biological barriers. However, some challenges are related to the clinical application of native exosomes. These challenges have led to advances in the engineering of exosomes. Surface modifications, cargo loading techniques, and hybridization with synthetic materials are some examples of these modifications. This review article explores innovative strategies to enhance the therapeutic potential of these exosomes. It focuses on modifying stem cells during the culture phase using techniques such as hypoxic preconditioning, chemical stimulation, and biophysical stimulation, which have been shown to optimize the quantity and biological activity of exosomes. Additionally, post-production modifications, including surface functionalization, hybridization with synthetic materials, and cargo enhancement, are being investigated for their role in improving the stability, targeting specificity, and therapeutic efficacy of exosomes. Together, these insights offer a roadmap for realizing the full potential of exosomes as next-generation delivery tools in nanomedicine.

Keywords:  Cell engineering; Drug delivery systems; Exosomes; Molecular targeted therapy; Nanomedicine

DOI:  https://doi.org/10.1016/j.bbrc.2026.153533
Adv Healthc Mater. 2026 Mar 18. e04014

Scalable Production of Multi-Source Hybrid Biomimetic Exosomes Co-Loaded with Therapeutic Plasmids for Treatment of High-Altitude Pulmonary Edema.

Sujia Si, Hong Wang, Ya Xu, Jian Wang, Ling Sun, Lu Zhang, Mengjun Zeng, Jianling Zhao, Hairong Yu, Riguang Zhao, Liqun Jiang.

  Exosomes show therapeutic promise but face limitations in simultaneous targeting and potency. While hybrid exosome strategies combining multiple cell components can address this, current methods rely on native exosome extraction and drug loading, suffering from low yield and encapsulation efficiency. We developed a biological origin-based hybrid biomimetic exosome (BOB-HBE) platform that synthetically assembles exosomes using parent cell-derived components through a water/oil/water emulsion method, overcoming production bottlenecks. For high-altitude pulmonary edema (HAPE) treatment, we engineered hybrid exosomes combining: (1) vascular endothelial cell membranes for lung targeting, (2) mesenchymal stem cell factors for regeneration, and (3) eNOS-encoding plasmid DNA to restore nitric oxide signaling. The BOB-HBE platform achieved >150-fold higher production yield than natural exosome isolation while enhancing pulmonary endothelial specificity. In HAPE models, these hybrid exosomes demonstrated triple therapeutic effects: restoring NO bioavailability, inhibiting pathogenic HIF-1α/TGF/Smad1/5 signaling, and preventing endothelial-mesenchymal transition and vascular remodeling. Consequently, they significantly attenuated HAPE progression by addressing both molecular pathways and tissue-level pathology. This study establishes a scalable platform for constructing multifunctional exosome mimetics that maintain native exosome advantages while solving key production challenges. The cell-origin-informed design strategy offers a versatile approach for targeted therapy in pulmonary and vascular disorders, with potential clinical translation advantages.

Keywords:  BOB‐HBE technology; eNOS genes; high‐altitude pulmonary edema; hybrid biomimetic exosome

DOI:  https://doi.org/10.1002/adhm.202504014
CNS Neurosci Ther. 2026 Mar;32(3): e70784

Exosome-Loaded Engineered circBDNF Promotes Spinal Cord Injury Repair Through the PI3K/AKT/mTOR Signaling Axis.

Gang Li, Ganggang Kong, Cheng Gu, Di Zhang, Yong Wan, Baoshu Xie.

   BACKGROUND: The brain-derived neurotrophic factor (BDNF) is a potent neuroprotective factor; however, its large molecular size limits its ability to cross structural barriers such as the blood-spinal cord barrier. This study explores the therapeutic potential of exosome-mediated delivery of engineered circular BDNF (circBDNF) to promote spinal cord injury (SCI) repair through activation of the PI3K/AKT/mTOR signaling pathway.
METHODS: A synthetic circBDNF sequence encoding BDNF was used to construct a circBDNF overexpression plasmid, which was transfected into HEK293T cells to generate circBDNF-loaded exosomes (circBDNF-EXO). These exosomes were characterized via transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. In vitro, the protective effects of circBDNF-EXO were evaluated in an oxygen-glucose deprivation/reperfusion (OGD) injury model in HT22 cells, focusing on cell viability, reactive oxygen species (ROS) levels, apoptosis, inflammation, and signaling pathways. In vivo, a T10 SCI mouse model was employed to assess therapeutic efficacy, using behavioral, electrophysiological, histological, and molecular analyses.
RESULTS: In vitro, circBDNF-EXO treatment significantly increased BDNF expression, enhanced cell viability, reduced ROS levels, mitigated inflammation, and inhibited apoptosis in HT22 cells following OGD injury. In vivo, administration of circBDNF-EXO resulted in improved motor function recovery, evidenced by increased Basso Mouse Scale scores, enhanced gait coordination, and better motor-evoked potentials. Histological analyses demonstrated elevated BDNF expression, decreased apoptosis, reduced oxidative stress, and enhanced axonal regeneration in the injured spinal cord. Mechanistically, circBDNF-EXO activated TrkB receptors and upregulated the PI3K/AKT/mTOR signaling pathway, as confirmed by Western blot analysis.
CONCLUSION: Exosome-mediated delivery of circBDNF promotes SCI repair by activating the PI3K/AKT/mTOR pathway, suppressing apoptosis, oxidative stress, and inflammation, and enhancing axonal regeneration. This innovative approach holds substantial promise for SCI treatment and deserves further exploration in preclinical and clinical studies.

Keywords:  PI3K/AKT/mTOR; circBDNF; exosomes; neuroprotection; spinal cord injury

DOI:  https://doi.org/10.1002/cns.70784
Biomater Res. 2026 ;30 0329

Intradermal Delivery of Catalase via Extracellular Vesicles for Targeted Photoaging Therapy.

Pengchen Zhang, Bo Pan, Jiayi Chen, Hao Jiang, Xinhe Wang, Yiyou Chen, Wei Wang, Ming Li, Qingyu Zeng, Zhaogang Yang.

The therapeutic potential of protein-based drugs is often limited by challenges in delivery, including instability, rapid degradation, and poor tissue targeting. Extracellular vesicles (EVs), as naturally derived nanocarriers, offer distinct advantages including biocompatibility, low immunogenicity, and efficient intercellular communication. Here, we engineered a 313 cell line to stably produce catalase (CAT)-loaded EVs (313EVs) that maintained vesicle integrity, exhibited high loading efficiency, and preserved enzymatic activity. Transcriptomic profiling revealed that genetic engineering subtly reshaped EV microRNA cargo, enriching 313EVs in pathways associated with EV uptake, mitochondrial membrane recovery, and DNA repair-supporting their multifaceted roles in mitigating photoaging. Functionally, 313EVs alleviated oxidative stress and restored antioxidant capacity in UVB-damaged fibroblasts. In vivo, intradermal administration resulted in sustained CAT activity, uniform dermal distribution, and marked improvements in wrinkle formation, collagen preservation, and skin elasticity. Notably, depletion of the skin microbiota did not alter therapeutic efficacy, indicating that the therapeutic benefits of 313EVs arise primarily from vesicle-intrinsic mechanisms rather than host-microbe interactions. Collectively, these findings establish 313EVs as a robust and versatile protein-delivery platform and highlight their therapeutic potential for combating oxidative stress-driven skin aging.

DOI: https://doi.org/10.34133/bmr.0329
Adv Healthc Mater. 2026 Mar 19. e03711

Potential Strategies for Bacterial Infection Control: Outer Membrane Vesicle Based Bacterial Vaccines.

Qingzhe Li, Lifei Guo, Li Fan, Heng Li, Jingxiang Wang, Guodong Yang, Xuekang Yang.

  Bacterial infections are the second leading cause of death worldwide. In particular, the increase of bacterial resistance and the emergence of superbacteria have put forward urgent requirements for the prevention and treatment of infection. Bacterial vaccines are considered as an effective strategy to prevent infection. Bacterial outer membrane vesicles (OMVs) are nanoscale spherical membrane structures produced by bacteria, containing a variety of bioactive substances, such as lipopolysaccharides, peptidoglycans, lipoproteins, etc. Due to its inherent adjuvant properties and antigen delivery ability, it can enhance humoral and cellular immune response, thereby improving the deficiency of low immunogenicity of vaccines. Moreover, OMV surface can be engineered to carry and display a variety of antigens. These advantages make OMV an ideal platform for developing innovative vaccines. In this review, followed by description of the classification, advantages and disadvantages of existing bacterial vaccines, the principles and challenges of OMV-based bacterial vaccines are discussed, providing new ideas for the treatment of infectious diseases.

Keywords:  bacterial infection; immune modulation; outer membrane vesicles; vaccines

DOI:  https://doi.org/10.1002/adhm.202503711
J Cancer Res Clin Oncol. 2026 Mar 17. pii: 68. [Epub ahead of print]152(3):

Exosome-based vaccines in cancer immunotherapy: antitumor mechanisms, engineering strategies, and challenges.

Huanling Zhou, Yuanxin Shi, Yueyue Wang, Guohui Bai.

  Exosome-based vaccines hold significant promise in cancer immunotherapy, yet their native forms face inherent challenges, including imprecise targeting, suboptimal immunogenicity, and poor controllability of antigen loading. This review posits that engineering is pivotal to transforming exosomes from passive carriers into active, programmable therapeutic platforms. We systematically dissect the multifaceted antitumor mechanisms of exosomes and critically evaluate how various engineering strategies (e.g., physical loading, genetic modification, membrane functionalization) are designed to address these specific biological bottlenecks, thereby establishing a coherent "biological limitation-engineering solution" framework. Building on this foundation, we assess their application potential and ongoing challenges in areas such as personalized neoantigen vaccines.

Keywords:  Exosomes; Immune response; Tumors; Vaccines

DOI:  https://doi.org/10.1007/s00432-026-06435-7
Mater Today Bio. 2026 Apr;37 102999

An exosome-biomimetic photothermal nanocarrier for IGF2BP2 siRNA delivery and enhanced ferroptosis in head and neck squamous cell carcinoma.

Mengmeng Li, Die Hu, Congge Tan, Ou Peng, Qian Yang, Yekai Feng, Yuming Zhang, Yonghang Zhang, Bingbing Zhang, Lanjie Lei, Shisheng Li.

  Head and neck squamous cell carcinoma (HNSCC) commonly develops treatment resistance, highlighting the necessity of novel therapeutic strategies. Although ferroptosis has emerged as a promising route, its regulatory determinants and effective gene delivery approaches in HNSCC remain poorly understood. In this study, we determined that the RNA-binding protein IGF2BP2 promotes ferroptosis resistance in HNSCC, at least in part by associating with increased NRF2 mRNA stability and sustaining the NRF2-SLC7A11/GPX4 antioxidant axis. Actinomycin D chase assays further support an IGF2BP2-dependent post-transcriptional regulation of NRF2 under erastin-induced ferroptotic stress. To therapeutically target this pathway, we engineered a biomimetic hybrid nanocarrier (si@PLE) by fusing M1 macrophage-derived exosomes with photothermally responsive cationic liposomes for the targeted delivery of IGF2BP2 small interfering RNA (siRNA). si@PLE exhibited favorable physicochemical properties and stability, and exosome-liposome fusion improved siRNA protection and tumor accumulation compared with that of the matched non-fused control, enabling enhanced tumor-site heating under identical irradiation conditions. In vitro and in vivo, si@PLE combined with near-infrared laser irradiation enhanced ferroptosis relative to either monotherapy, significantly suppressing tumor growth with a favorable safety profile. Collectively, these findings establish a biomimetic gene silencing-photothermal platform to sensitize HNSCC to ferroptosis by targeting the IGF2BP2-NRF2 axis.

Keywords:  Ferroptosis; Gene therapy; Head and neck squamous cell carcinoma; Photothermal therapy

DOI:  https://doi.org/10.1016/j.mtbio.2026.102999
J Nanobiotechnology. 2026 Mar 16.

Dual-targeted hybrid nanovesicles coordinated bone-muscle regeneration via regulating the DUSP4/p38 MAPK pathway to reverse osteosarcopenia.

Benchi Che, Yongzhi Cui, Zhengsheng Chen, Yanchun Gao, Lei Luo, Kaiwen Zheng, Jiashuo Liu, Yu Xiang, Jiaqi Cheng, Yuanyuan Guo, Qing Li, Dehao Fu.

  Osteosarcopenia (OSP), a degenerative syndrome characterized by concurrent osteoporosis and sarcopenia, exhibits persistently high global prevalence due to aging and disuse, yet lacks targeted therapies. p38 MAPK plays a key regulatory role in musculoskeletal degeneration. Increased expression of DUSP4, a key inhibitor of the Mitogen-Activated Protein Kinase (MAPK) pathway, inhibits the phosphorylation of p38 MAPK. Thus, targeted delivery of microRNAs that inhibit DUSP4 expression can activate the p38 MAPK pathway and promote osteogenic and myogenic differentiation. However, the therapeutic efficacy of nucleic acid drugs critically depends on delivery systems with targeted specificity, stability, and biocompatibility. Therefore, we engineered a hybrid nanovesicle (miR@DT/iMNV) by fusing bone-muscle dual-targeting peptide-modified liposomes (miR@DT-Lipo) and iPSC-derived MSC-EVs (iMSC-EVs). The miR@DT/iMNV enables the dual-tissue targeted delivery of miR-206-5p (which is downregulated in OSP and can target and inhibit DUSP4) and exhibits excellent biocompatibility. Results demonstrated that miR@DT/iMNV enhances osteogenic/myogenic capacities of stem cells, modulates macrophage phenotypes, restores mitochondrial function, and increases bone/muscle mass in a disused OSP murine model. This dual-targeted, multi-mechanistic strategy presents an innovative therapeutic approach for OSP.

Keywords:  DUSP4; Dual-targeted delivery; Extracellular vesicles; Hybrid vesicles; Osteosarcopenia; microRNA; p38 MAPK

DOI:  https://doi.org/10.1186/s12951-026-04279-4
Front Pharmacol. 2026 ;17 1784404

Extracellular vesicles delivering TIMP-2 modulate MMP-1, MMP-2, and MMP-9 expression in human lung adenocarcinoma A549 cells.

Agnieszka Stawarska, Magdalena Bamburowicz-Klimkowska, Maciej Małecki, Anna M Nowicka, Żaneta Słyk, Agata Kowalczyk, Alicja Targonska, Ireneusz P Grudzinski.

   Background/Objectives: Extracellular vesicles (EVs) carrying therapeutic cargos represent a promising strategy for cancer treatment by enabling the targeted delivery of genetic material directly to cancer cells. This study aimed to evaluate the effect of EVs loaded with the TIMP-2 gene on the expression of matrix metalloproteinases (MMPs 1, 2, and 9) in lung cancer cells (A549).
Methods: EVs derived from A549 cells were isolated by gradient centrifugation and ultracentrifugation. The coding sequence for TIMP-2 (tissue inhibitor of metalloproteinases 2) was amplified by PCR using cDNA derived from HUVEC cells. As-constructed plasmid (pTIMP-2) was introduced into the EVs by electroporation, and then the pTIMP-2-implanted EVs were subjected to PCR and NTA analysis. Additionally, the activity of MMP-1, MMP-2, and MMP-9 was determined by voltammetry in intact A549 cells and in A549 culture media.
Results: Electroporation was found to demonstrate a good potential as an exogenous technique for uploading plasmid DNA into EVs. The results demonstrated that the as-uploaded EVs carrying the pTIMP-2 gene cargo do not broadly alter the overall balance of MMP-1 in pristine A549 cells. However, pTIMP-2-loaded EVs significantly modulate MMP-2 and MMP-9 expression in these cells, highlighting their potential as biological therapeutic moieties.
Conclusion: Our findings suggest a rational approach for exploring EV-based gene transfer targeting MMPs in lung cancer.

Keywords:  electroporation; extracellular vesicles; gene encapsulation; lung cancer cells; matrix metalloproteinases; tissue inhibitor of metalloproteinase

DOI:  https://doi.org/10.3389/fphar.2026.1784404
CNS Neurol Disord Drug Targets. 2026 Mar 12.

Pharmacological Breakthroughs with Extracellular Vesicles-Based Nanomedicine: A Targeted Strategy to Cross the Blood-Brain Barrier in Alzheimer's Disease.

Jasmeen Kaur, Dushyant, Smita Narwal, Gurvirender Singh, Rupa Devi, Tavleen Kaur, Nisha Grewal, Ashwani K Dhingra.

  Alzheimer's Disease (AD) is a disabling neurodegenerative illness characterized by Amyloid-beta (Aβ) plaque deposition, tau tangles, and neuroinflammation. These pathological characteristics lead to progressive cognitive decline, and drug therapeutic approaches are bedeviled by extreme difficulty with the Blood-Brain Barrier (BBB) that prevents most drugs from effectively crossing into the brain. Extracellular vesicle-based nanomedicine is a prospective approach to overcome this hurdle. Extracellular vesicles are endogenously derived extracellular vesicles that can cross the BBB and deliver a variety of therapeutic cargos, including small interfering RNAs (siRNAs), microRNAs (miRNAs), proteins, and other small molecules. Since they can cross the BBB and exhibit low immunogenicity and toxicity, extracellular vesicles represent a promising strategy for drug delivery against AD. Recent studies have highlighted the potential of extracellular vesiclebased treatments to deliver anti-amyloid and anti-tau therapies, neuroprotectants (e.g., antioxidants), and immune-modulatory factors. Engineered extracellular vesicles containing siRNA against βsecretase eta-site app cleaving enzyme 1 (BACE1), anti-tau oligonucleotides, and anti-inflammatory cytokines have shown promising preclinical efficacy by reducing Aβ deposition, tau aggregation, and neuroinflammation. These changes have been associated with enhanced cognitive function. Besides, extracellular vesicle-based systems were investigated for gene-editing therapeutics with Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/ Cas9) and Antisense Oligonucleotides (ASOs). Besides scalability concerns, cargo-loading efficiency, and long-term toxicity, extracellular vesicle-based nanomedicine is an innovative platform for targeted drug deli.

Keywords:  Alzheimer's disease; amyloid-beta; blood-brain barrier; nanomedicine; neuroprotective molecules; therapies.

DOI:  https://doi.org/10.2174/0118715273418647251208093957
Colloids Surf B Biointerfaces. 2026 Mar 12. pii: S0927-7765(26)00186-4. [Epub ahead of print]264 115598

Milk exosomes delivery of KPT-330 alleviates gastrointestinal adverse reactions and provides effective anti-diffuse large B-cell lymphoma therapy.

Yali Chai, Ran Xue, Xingming Peng, Yilei Shi, Qi Li, Si Chen, Lexin He, Meifang Zhao, Yuchen Zhang, Hongxia Cui, Chuan He, Han Zhang, Bingzong Li, Wenzhuo Zhuang.

  The FDA granted accelerated approval to KPT-330 (selinexor) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, 80% of patients experienced gastrointestinal toxicity. Milk exosomes (mExos) possess high stability in the gastrointestinal environment and the ability to traverse the gastrointestinal barrier, making them an excellent choice for oral drug delivery. Here, we isolated and identified mExos, which demonstrated good stability in simulated fed-state gastrointestinal fluids. These exosomes effectively encapsulated KPT-330, enhancing drug accessibility within DLBCL and sustaining intracellular accumulation over an extended period. mExo-KPT-330 showed a slight increase in size, with no apparent changes in shape or biological characteristics. mExo-KPT-330 outperformed free KPT-330 in vitro, exhibiting a more potent DLBCL-suppressive effect. Furthermore, in DLBCL mouse models, mExo-KPT-330 exhibited a significantly reduced disease burden compared to free KPT-330. Notably, mExo-KPT-330 alleviated the disorganization of the intestinal epithelium, edema in the villous stroma of the small intestine, lymphocyte infiltration, and elevated serum levels of LPS and IL-12 caused by free KPT-330 treatment. Additionally, mExo-KPT-330 exhibited no organ toxicity. Encapsulating KPT-330 in mExos significantly increased its permeability across the intestinal epithelial barrier. Moreover, mExo-KPT-330 maintained its intact exosomal form after being transported across the intestinal epithelial barrier. Collectively, our results suggest that mExo loaded with KPT-330 has promising anti-DLBCL effects and that oral administration is beneficial for alleviating gastrointestinal adverse reactions induced by KPT-330.

Keywords:  Diffuse large B-cell lymphoma; Drug delivery system; Gastrointestinal Adverse Reactions; KPT-330; Milk exosomes

DOI:  https://doi.org/10.1016/j.colsurfb.2026.115598