bims-engexo 2026-08-02 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–08–02
eleven papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Exosome-Mediated Delivery of PROTACs for Targeted Protein Degradation in Cancer, Neurodegenerative, Infectious, and Inflammatory Diseases.
Functional Engineered Exosomes Loaded with Nanoenzymes Targeting the Proteasome and Inflammation for the Treatment of Rheumatoid Arthritis.
Engineered Bacterial Membranes as Next-Generation Platforms for Cancer Immunotherapy.
Engineered exosomes improve myocardial cell membrane integrity and heart function in dystrophic cardiomyopathy.
Microfluidic Platforms for Exosome Engineering: Scalable Therapeutics for Cancer Immunotherapy and Infectious Diseases.
Engineered extracellular vesicles derived from sweet potato loaded with siPOLD1 for targeted therapy of glioma.
Membrane Fusion-Based Mirabilis Himalaica-Derived Exosome-like Nanoparticles Fused with Cell-Penetrating Peptide Mediated for Chebulinic Acid Delivery Against UVA-Induced Photoaging.
A Chemical Framework for Engineering Extracellular Vesicles' Biointerface to Advance Precision Therapeutics.
Exosomes delivering a high-throughput-screened RNA polymerase inhibitor for highly effective therapy of multidrug-resistant bacterial infected pneumonia.
Extracellular vesicles as vaccine platforms: emerging opportunities for malaria.
TRIM27-Cas9-loaded EVs suppress HCC proliferation and enhance responsiveness to anti-PD-1 therapy by promoting ACSL4-mediated ferroptosis.

J Cell Mol Med. 2026 Aug;30(15): e71297

Exosome-Mediated Delivery of PROTACs for Targeted Protein Degradation in Cancer, Neurodegenerative, Infectious, and Inflammatory Diseases.

Sruti Bagchi Ghosh, Rumpa Banerjee, Hailah M Almohaimeed, Amany I Almars, Tahani Ahmad ALMatrafi, Fayez M Saleh, Zuhair M Mohammedsaleh, Kranti Kiran Reddy Ealla, Ajoy Kumer, Bikram Dhara.

  Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that hijack the ubiquitin-proteasome system to drive catalytic, sub-stoichiometric degradation of disease-associated proteins, offering a mechanistic advantage over occupancy-driven inhibitors and access to 'undruggable' targets. However, their clinical translation is constrained by high molecular weight, poor solubility, low oral bioavailability, inefficient membrane permeability, nonspecific biodistribution, off-target degradation, and the concentration-dependent 'hook effect.' Exosomes, nanoscale extracellular vesicles with innate biocompatibility, low immunogenicity, prolonged circulation, and the ability to cross barriers such as the blood-brain barrier, offer a biologically integrated platform to overcome these limitations. This review traces the evolution of PROTAC technology, delineates the challenges of conventional delivery, and evaluates the rationale for exosomal encapsulation, including cargo protection, intracellular trafficking, endosomal escape, and release kinetics. We examine natural and engineered exosomes spanning source selection, active loading strategies, and surface functionalization for tissue-specific homing and synthesize therapeutic applications across viral infections, cancer, neurodegenerative disorders, and inflammatory diseases. Proof-of-concept studies, such as camel milk-derived exosomes delivering the BRD4-targeting PROTAC ARV-825, demonstrate enhanced permeability, lower IC50 values, and improved oral bioavailability. Finally, we discuss key hurdles to clinical translation: scalable production, purification, and standardization, and outline future directions for exosome-mediated targeted protein degradation.

Keywords:  PROTACs; drug delivery; engineering strategies; exosomes; heterobifunctional; therapeutic applications

DOI:  https://doi.org/10.1111/jcmm.71297
Small. 2026 Jul 29. e74907

Functional Engineered Exosomes Loaded with Nanoenzymes Targeting the Proteasome and Inflammation for the Treatment of Rheumatoid Arthritis.

Ensi Liu, Chang Shen, Qiannan Zhao, Shuai Cheng, Wei Wang, Huicong Feng, Zhen Dai, Zhaoliang Shen, Sen Lin, Xifan Mei.

  Mesenchymal stem cell -derived exosomes (MSCs-EXO) have been increasingly studied due to their high biosafety and excellent drug delivery properties. The use of MSCs-EXO as drug carriers for the treatment of rheumatoid arthritis (RA) has been reported. However, conventional exosomes cannot target the damaged area, significantly reducing their therapeutic efficacy. Therefore, this study proposes a strategy for the rational design of exosomes derived from genetically engineered mesenchymal stem cells, enabling them to target the inflammatory storm in the affected limb, regulate the immune microenvironment, and release similar to superoxide dismutase (SOD-like) and similar to catalase (CAT-like) nanoparticles to eliminate Reactive Oxygen and Nitrogen Species (RONS). RA provides a therapeutic platform for disease repair. MSC transduced with a lentivirus and carrying the anchoring peptide IL-4Rα secrete exosomes containing this peptide (IL-4.EXO), which demonstrates excellent targeting ability. These exosomes encapsulate Prussian blue nanoparticles (PB@IL-4.EXO), forming a synergistic composite exosome delivery system targeting inflammation sites, antioxidant stress, and promoting cartilage joint repair. Micro-CT shows a reduction in cartilage damage. Proteomics confirmed that it inhibits inflammation by affecting the proteasomal pathway through suppression of the PSMD4 protein. This exosome combines regulation of inflammation and antioxidant stress, offering a new therapeutic strategy for RA.

Keywords:  eliminate RONS; mesenchymal stem cell‐derived exosomes; regulate macrophage polarization; regulating the immune microenvironment; regulation of oxidative stress

DOI:  https://doi.org/10.1002/smll.74907
Small Sci. 2026 Aug;6(8): e70351

Engineered Bacterial Membranes as Next-Generation Platforms for Cancer Immunotherapy.

Hafiza Aasia Malik, Urooj Yousaf Virk, Mohamed Salah Attia, Jenny Wilson, Ming Wei.

  Bacterial membranes, in their natural and engineered forms, including outer membrane vesicles, bacterial ghosts, engineered membrane fragments, and hybrid scaffolds, are emerging as multifunctional immunotherapeutic platforms that merge antigen presentation with intrinsic adjuvanticity. By codisplaying tumor antigens and conserved pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide, flagellin, and CpG motifs, bacterial membranes activate dendritic cells, drive crosspresentation, and elicit durable cytotoxic T-cell memory. Advances in genetic fusion systems (Lpp-OmpA, ClyA, Ag43, and SpyTag/SpyCatcher), lipid A detoxification, and tumor membrane hybridization have transformed bacterial membranes from empirical immunostimulants into programmable vaccine scaffolds. Preclinical studies across melanoma, lung, breast, and glioblastoma models show that these systems reprogram the tumor microenvironment, inducing Th1-polarized immunity, pyroptotic tumor death, and synergy with checkpoint blockade, chemotherapy, and phototherapy. Beyond vesicular formats, membrane fragments and engineered ghosts demonstrate equivalent potential for safe, modular, and scalable vaccine design. Integrating AI-driven antigen discovery, CRISPR-based strain engineering, and automated biofoundries now offers a path toward clinical translation. Collectively, these developments position bacterial membranes as a unifying platform that bridges innate and adaptive immunity for next-generation cancer immunotherapy.

Keywords:  bacterial ghosts (BGs); bacterial membrane‐based vaccines; cancer immunotherapy; immune modulation; nanovesicle engineering; neoantigen vaccines; outer membrane vesicles (OMVs); tumor microenvironment

DOI:  https://doi.org/10.1002/smsc.70351
Clin Transl Med. 2026 Aug;16(8): e70751

Engineered exosomes improve myocardial cell membrane integrity and heart function in dystrophic cardiomyopathy.

Qihong Wu, Yiyuan Xue, Kun Zhang, Ke Xu, Ting Xu, Hang Fu, Suming Zhang, Meng Zhang, Ran Sun, Sophelia Hoi Shan Chan, Linyuhan Zhou, Xiaotang Cai, Yingkun Guo, Huayan Xu.

   BACKGROUND: Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a leading causes of premature death, yet treatment options remain limited. In this study, we developed the easily accessible engineered exosomes for treatment of DMD-associated cardiomyopathy and explored the underlying mechanisms in DmdΔ4 mice, a model harboring hot spot mutation in the dystrophin gene.
METHODS: DmdΔ4 mice and their cardiomyopathy phenotype were confirmed by Sanger sequencing, pathological staining, flow cytometry, immunoblotting, single-cell sequencing and echocardiographic analysis. Engineered exosomes, exosomes- cardiac homing peptide (Exo-CHP), were synthesised and characterised by click chemistry and miRNA sequence, separately. The targeted ability and the therapeutic effects of Exo-CHP were studied in vitro and in vivo. Primary cardiomyocytes were used to study the underlying mechanism of Exo-CHP.
RESULTS: DmdΔ4 mice showed an obvious cardiomyopathy-associated phenotype. Exo-CHP can target myocardium and mitigate pathological progression of cardiomyopathy in DmdΔ4 mice. The therapeutic effects of intravenously delivered Exo-CHP significantly reduced myocardial inflammation, fibrosis and improved the mice's cardiac function. The rescue effects were mediated through the regulation of gene expression at the transcriptomic level, prevention of dystrophin protein complex degradation, and inhibition of intracellular calcium influx and calpain protease activity. The miR-21 knockdown Exo-CHP can counteract the protective effects of Exo-CHP on the calcium content and membrane integrity of primary DmdΔ4-derived cardiomyocytes.
CONCLUSIONS: Our study demonstrated the feasibility, efficacy and the possible mechanism of mesenchymal stromal cell-derived engineered exosomes, positioning them as a potential cell-free intervention for DMD-associated cardiomyopathy.

Keywords:  Duchenne muscular dystrophy; cardiomyopathy; engineered exosomes; mesenchymal stromal cells

DOI:  https://doi.org/10.1002/ctm2.70751
Int J Mol Sci. 2026 Jul 15. pii: 6298. [Epub ahead of print]27(14):

Microfluidic Platforms for Exosome Engineering: Scalable Therapeutics for Cancer Immunotherapy and Infectious Diseases.

Minyoung Lee, Kwangmin Park, Jungho Kim, Kyung-A Hyun, Anbazhagan Sathiyaseelan, Sunyoung Park.

  Extracellular vesicles (EVs), particularly small EVs or exosomes, are promising cell-free therapeutics with superior biocompatibility and intrinsic targeting for synthetic nanoparticles. However, conventional bulk preparation methods suffer from low yield, poor reproducibility, and structural instability. Microfluidic technologies resolve these issues by enabling precise, automated, and low-shear fluidic manipulation. This mini-review highlights recent advances in microfluidic-engineered exosomes for cancer immunotherapy and infectious diseases. We evaluate critical microfluidic strategies for isolation, surface engineering, and cargo loading, contrasting platforms like ExoArc, acoustofluidics, cellular nanoporation, and electroporation. Particular emphasis is placed on complex modalities, including immune cell-derived exosomes (IEX), neo-antigen presentation, chimeric antigen receptor (CAR)-derived exosomes, and targeted siRNA delivery networks. Crucially, we analyze the technological disconnect between analytical microfluidic scales and massive therapeutic manufacturing volumes, addressing how physical forces risk damaging conformationally sensitive surface proteins (e.g., CAR scFv). Finally, we outline future perspectives, including high-throughput 3D-multiplexed networks, stimulus-responsive scarless elution, and integrated "sample-to-therapy" circuits. Guided by the MISEV2023 guidelines, this review frames the path toward standardized, clinical-scale engineering of multi-functional, cell-free immunotherapies.

Keywords:  cancer immunotherapy; clinical translation; exosomes; infectious disease vaccines; microfluidic engineering

DOI:  https://doi.org/10.3390/ijms27146298
J Adv Res. 2026 Jul 26. pii: S2090-1232(26)00606-5. [Epub ahead of print]

Engineered extracellular vesicles derived from sweet potato loaded with siPOLD1 for targeted therapy of glioma.

Zhiyong Jin, Shan Jiang, Liujie Yuan, Sicheng Ma, Feifan Zhang, Mengyao Zhu, Gang Li, Rutong Yu.

   INTRODUCTION: Glioma is the most common malignant tumor of the central nervous system, with high malignancy and poor prognosis, necessitating the development of novel targeted therapies. DNA polymerase delta catalytic subunit 1 (POLD1) is implicated in multiple cancers, but its role in glioma remains unclear. Plant-derived extracellular vesicles (PDEVs) have emerged as biocompatible, targetable nanocarriers with promising applications in cancer therapy.
OBJECTIVE: This study aims to elucidate the oncogenic function of POLD1 in glioma and develop a PDEVs -based delivery system for targeted therapy, with the goal of improving the current therapeutic landscape for glioma.
METHODS: POLD1 expression and prognostic significance were analyzed using clinical samples and databases. In vitro, CCK-8, Transwell, and flow cytometry assays evaluated the impact of POLD1 knockdown on glioma cell proliferation, invasion, migration, cell cycle, and apoptosis. In vivo tumorigenesis and survival were assessed in mouse models. Sweet potato-derived nano-vesicles (SPDELNVs) were isolated and characterized. An engineered A2-SPDELNVs-siPOLD1 system was developed via surface modification and siRNA loading, and its targeting efficiency and therapeutic efficacy were evaluated both in vitro and in vivo.
RESULTS: POLD1 was upregulated in glioma tissues and correlated with poor prognosis. Its knockdown suppressed proliferation, invasion, and migration, induced cell cycle arrest, and promoted apoptosis in vitro. In vivo, POLD1 targeting inhibited tumor growth and prolonged survival. SPDELNVs showed intrinsic anti-glioma activity and efficient cellular uptake. The engineered A2-SPDELNVs-siPOLD1 effectively delivered siRNA, silenced POLD1, and significantly inhibited tumor progression both in vitro and in vivo, with enhanced survival.
CONCLUSION: Our findings uncover the oncogenic role of POLD1 in glioma and validate it as a promising therapeutic target. Furthermore, we establish a novel, plant-based A2-SPDELNVs-siPOLD1 delivery platform with effective BBB penetration and tumor targeting, offering a promising strategy for the treatment of glioma.

Keywords:  Blood-brain barrier; Glioma; POLD1; Plant-derived extracellular vesicles; Targeted therapy; siRNA delivery

DOI:  https://doi.org/10.1016/j.jare.2026.07.062
Cells. 2026 Jul 08. pii: 1235. [Epub ahead of print]15(14):

Membrane Fusion-Based Mirabilis Himalaica-Derived Exosome-like Nanoparticles Fused with Cell-Penetrating Peptide Mediated for Chebulinic Acid Delivery Against UVA-Induced Photoaging.

Weiwei Zhao, Siqi Yang, Ruobing Liu, Chaozhi Liu, Jing Zhang, Ying Liu, Guihong Sun, Mingxiong Guo.

  Exposure to ultraviolet (UV), particularly UVA radiation, is a primary driver of photoaging due to its deep dermal penetration, which triggers DNA damage, collagen degradation, and immune suppression. Chebulinic acid (CA), a polyphenolic compound from Terminalia chebula, exhibits potent antioxidant and anti-inflammatory properties against UVB-induced skin damage. However, its large molecular weight hinders transdermal delivery and the TAT47-57 peptide (core of HIV-1 TAT) enables rapid transmembrane transport. Large particles with double-layer membrane structure and a diameter exceeding 1000 nm were obtained during the separation of plant-derived exosome-like nanoparticles (PELNs), which are not considered as PELNs (50-500 nm), after a mixture with TAT anchored to the surface of engineered artificial vesicles (EAVs) and extrusion causes membrane fusion, employed as novel nanocarriers to overcome the difficulty in skin penetration by leveraging their lipid bilayer structure and surface membrane-anchored TAT for efficient epidermal fusion and intercellular penetration. Furthermore, CA-loaded TAT-ePELNs demonstrate significant efficacy in mitigating UVA-induced photoaging. Collectively, this study expands the anti-UVR damage application spectrum of CA from UVB to UVA exposure and establishes a green, efficient, and biosafe strategy for transdermal drug delivery by utilization of non-PELNs generated during the preparation process of PELNs.

Keywords:  TAT peptide; anti photoaging; chebulinic acid; plant-derived exosome-like nanoparticles

DOI:  https://doi.org/10.3390/cells15141235
Adv Mater. 2026 Jul 25. e74203

A Chemical Framework for Engineering Extracellular Vesicles' Biointerface to Advance Precision Therapeutics.

Leila Pourtalebi Jahromi, Felix Geng, Jan-Noël Frenzke, Gregor Fuhrmann.

  Extracellular vesicles (EVs) are membrane-bound nanoparticles ubiquitously secreted by all cell types and serve diverse physiological and pathological functions. Due to their pivotal roles in pathophysiological processes and their inherent biomimetic properties, EVs have attracted significant attention as biomarkers, as well as for tissue engineering and drug delivery. The surface chemistry of EVs dictates their interactions with their environment. Great strides have been made to tailor this biochemical interface with the aim of enhancing cargo delivery, target specificity, immune evasion, and tracking capabilities, while preserving EVs' stability and functional integrity. Approaches to surface modification primarily encompass genetic and metabolic manipulation of parent cells, application of physical forces, and chemical reactions. In this manuscript, we introduce a comprehensive chemistry-centric framework for EV surface engineering that integrates demonstrated EV modification strategies with protein- and cell-surface chemistries not yet applied to EVs, delineating their functional scope and translational potential for advancing EV-based therapeutics.

Keywords:  bioengineering; bioorthogonal chemistry; chemical biology; extracellular vesicles; surface engineering

DOI:  https://doi.org/10.1002/adma.74203
Bioact Mater. 2026 Dec;66 623-637

Exosomes delivering a high-throughput-screened RNA polymerase inhibitor for highly effective therapy of multidrug-resistant bacterial infected pneumonia.

Yiming Xiang, Ziya Gong, Juying Liu, Yizhou Zhu, Congyang Mao, Can Ai, Chaofeng Wang, Xiaofei Yang, Xiangmei Liu, Kelvin W K Yeung, Shuilin Wu.

  Bacterial pneumonia remains a primary global health threat, necessitating the development of novel therapeutic strategies to overcome escalating antibiotic resistance. In this study, we identified a highly active bacterial RNAP inhibitor, the repurposed semi-synthetic anthracycline hydrochloride Epirubicin (EPI), via the in silico high-throughput screening of a commercial library containing 16,563 small molecules. We identified EPI as a potent multi-target antibacterial agent. Alongside its intrinsic DNA intercalation properties, EPI heavily interferes with RNAP by targeting conserved catalytic residues (LYS838 and ASP1003), destabilizing the RNAP structure through a mechanism distinct from rifampicin. In vitro, EPI (8 μg/mL) achieved 99% eradication of S. aureus and multidrug-resistant (MDR) E. coli within 12 h by disrupting carbohydrate metabolism and ATP synthesis. To enhance clinical efficacy, EPI was encapsulated in stem cell-derived exosomes (Exo/EPI). In murine pneumonia models, the Exo/EPI nanoplatform cleared 99% of bacteria within 12 h. Furthermore, the platform rapidly attenuated infection-induced pulmonary inflammation, evidenced by a marked reduction in inflammatory cell infiltration, while significantly accelerating structural lung tissue repair and preventing cellular apoptosis via organized collagen deposition. This integrated strategy of computational discovery and exosomes delivery provides a blueprint for developing multifunctional antimicrobials against MDR infections.

Keywords:  Antibacterial; Bacterial pneumonia; Exosome-based nanoplatform; High-throughput screening; RNA polymerase inhibitor

DOI:  https://doi.org/10.1016/j.bioactmat.2026.07.023
Front Immunol. 2026 ;17 1870149

Extracellular vesicles as vaccine platforms: emerging opportunities for malaria.

Gisele Tatiane Soares da Veiga, Jordana Dinorá de Lima, Letusa Albrecht.

  Malaria is the deadliest parasitic disease worldwide, and the urgent need for preventive strategies remains unmet. The parasite poses unique challenges, as it exhibits remarkable epitope variability and undergoes genetic mutations that allow adaptation to control measures, including drug treatment, and high ability of immune system evasion. In addition, malaria frequently develops asymptomatic forms, which sustain silent transmission and perpetuate the disease burden. In this complex context, extracellular vesicles (EVs) have emerged as promising tools for vaccine development. EVs can be engineered to carry specific and various antigens and to exploit their natural ability to fuse with cell membranes, enabling effective delivery. Depending on their cargo, they can modulate immune responses in a tailored manner, reawakening host immunity and targeting the parasite even in dormant stages. Despite extensive advances in EV-based approaches for viral and cancer models, their application to neglected diseases, including malaria, remains limited. This review aims to discuss strategies for engineering EVs as vaccines, drawing on insights from other disease models and highlighting the unique features of malaria that could benefit from such an approach.

Keywords:  Plasmodium; engineered EVs; malaria; neglected diseases; prevention

DOI:  https://doi.org/10.3389/fimmu.2026.1870149
Cell Death Differ. 2026 Jul 27.

TRIM27-Cas9-loaded EVs suppress HCC proliferation and enhance responsiveness to anti-PD-1 therapy by promoting ACSL4-mediated ferroptosis.

Jie Wen, Zhihui Wang, Zhirui Zeng, Yu Tian, Haikuan Liu, Xiaokai Zhang, Shaoqing Niu, Milad Ashrafizadeh, Gautam Sethi, Wenpeng Cao, Xiaolin Wei, Shan Lei.

Inducing ferroptosis in hepatocellular carcinoma (HCC) cells represents an important therapeutic strategy, but intrinsic resistance mechanisms often limit efficacy. Therefore, elucidating the mechanisms underlying ferroptosis resistance in HCC cells can facilitate the development of effective therapeutic strategies. Here, we performed genome-wide CRISPR/Cas9 library screens to identify TRIM27 as a key determinant of ferroptosis resistance. TRIM27 knockdown markedly potentiated erastin-induced ferroptosis in HCC cells, whereas TRIM27 overexpression suppressed the expression of fatty-acid metabolic enzymes including ACSL4 and reduced oxidized lipid accumulation. Mechanistically, TRIM27 directly binds with ACSL4 and promotes its K48-linked ubiquitination and degradation, thereby attenuating ferroptosis in HCC cells. Furthermore, we developed TRIM27-Cas9-loaded EVs with robust editing efficiency. These engineered EVs were readily internalized by HCC cells and preferentially accumulated in the liver. Functionally, TRIM27-Cas9-loaded EVs inhibited HCC cell proliferation by enhancing ACSL4-mediated ferroptosis and significantly improved the anti-tumor efficacy of anti-PD-1 therapy in HCC. Collectively, our findings suggest that TRIM27 confers ferroptosis resistance via facilitating K48-linked ubiquitination and subsequent proteasomal degradation of ACSL4. TRIM27-Cas9-loaded EVs restore cellular sensitivity to ferroptosis, inhibit HCC proliferation, and sensitize HCC lesions to anti-PD-1 immunotherapy.

DOI: https://doi.org/10.1038/s41418-026-01824-4