bims-engexo 2026-10-11 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–10–11
eighteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Integrating Nanomaterials with Extracellular Vesicles: Engineering Strategies and Translational Perspectives.
Extracellular vesicles as biomimetic platforms for photo-assisted cancer therapy: evolution from synthetic nanocarriers to engineered therapeutic systems.
Engineering extracellular vesicles for multi-cargo co-delivery in silicosis and related fibrotic diseases: design strategies and translational prospects.
Engineered Extracellular Vesicles for Cartilage Regeneration: Bridging Biological Complexity to Clinical Precision.
Advances in Extracellular Vesicle-Based Innovative Drugs Targeting Alzheimer's Disease.
Coupling extracellular vesicles with nanomedicine for precision theranostics.
Recent advances in research on novel therapeutic mechanisms and strategies for exosome-based treatment of ischemic stroke.
Metabolically engineered chimeric probiotic-cancer vesicles orchestrate anti-tumor systemic immunity.
Fibroblastic Reticular Cell-Derived and CD5L-Enriched Exosomes Remodel Renal Lipid Metabolism in Porcine Sepsis-Associated Acute Kidney Injury.
Artificial Regulatory T Cells Orchestrate Phase-Spanning Regeneration in Refractory Tissue Injuries.
Engineered mesenchymal stem cell-derived small extracellular vesicles delivering miR-124 suppress colorectal cancer progression through EZH2 downregulation and attenuation of STAT3 signaling.
Engineered mesenchymal stem cell-derived extracellular vesicles as programmable biomaterial platforms for liver fibrosis: design principles, manufacturing and clinical translation.
Protocol for scalable production of orally deliverable R-spondin1-loaded small extracellular vesicles for WNT-signaling activation and tissue regeneration.
Rapid and Efficient Affinity Isolation of Engineered Extracellular Vesicles Encapsulating Functional Proteins via Internal Twin-Strep Tetraspanin Tagging.
Innovative myeloid ecotropic viral integration site 1-engineered exosome platform combating oxidative stress and inflammation in acute pulmonary damage.
Curcumin-loaded pH-responsive hybrid nanovesicles from Bergenia purpurascens root exosomes for synergistic lung cancer treatment.
Synergistic reversal of mesenchymal stem cell senescence by engineered exosomal delivery of a dual miR-195/miR-188 sponge.
Engineered Source-Specific Extracellular Vesicles for Neurodegenerative Diseases: From Biological Barriers to Targeted Delivery Strategies.

Nanotechnology. 2026 Oct 07.

Integrating Nanomaterials with Extracellular Vesicles: Engineering Strategies and Translational Perspectives.

Thi Hien Le, Le Minh Tu Phan.

  Extracellular vesicles (EVs), particularly stem cell-derived exosomes, serve as vital natural nanocarriers in regenerative medicine, immune modulation, and targeted drug delivery due to their innate ability to transport bioactive cargo across complex biological barriers. Despite this potential, the therapeutic efficacy of native EVs is frequently constrained by intrinsic limitations such as rapid systemic clearance, low loading efficiency, limited targeting specificity, and significant manufacturing hurdles. Integrating engineered nanomaterials provides a powerful synergistic strategy to enhance EVs systems through sophisticated engineering that improves structural stability, maximizes cargo loading, and introduces multifunctional capabilities like real-time imaging and stimuli-responsive release. The objective of this review is to systematically analyze rational design principles for nano-EV hybrid systems while evaluating the critical barriers to their clinical translation. Key themes discussed include diverse engineering strategies-ranging from surface functionalization to scaffold-based delivery-alongside therapeutic applications in oncology and regenerative medicine, safety assessments, and production standardization. Ultimately, these advanced nano-EV platforms signify a transformative direction for next-generation nanomedicine, offering intelligent and scalable solutions for precise, clinically translatable therapeutics.

Keywords:  Nanomaterials; exosome; extracellular vesicles; regenerative medicine; therapy

DOI:  https://doi.org/10.1088/1361-6528/aeb12e
Front Oncol. 2026 ;16 1955178

Extracellular vesicles as biomimetic platforms for photo-assisted cancer therapy: evolution from synthetic nanocarriers to engineered therapeutic systems.

Lucía Beaugé, Luis Exequiel Ibarra.

  Photo-assisted therapies have emerged as promising strategies for cancer treatment by combining localized tumor ablation with the induction of systemic antitumor immune responses. Despite encouraging preclinical and clinical advances, their therapeutic efficacy remains limited by the unfavorable pharmacokinetics, poor tumor selectivity, restricted tissue penetration, and off-target toxicity of conventional photosensitizer formulations. Although synthetic nanocarriers have substantially improved photosensitizer delivery, their limited biological functionality has driven the development of biomimetic drug delivery systems capable of actively interacting with the tumor microenvironment. Among these, extracellular vesicles have rapidly emerged as highly attractive therapeutic platforms owing to their intrinsic biocompatibility, prolonged circulation, natural tissue tropism, ability to cross biological barriers, and unique role in intercellular communication. In this review, we examine the evolution of extracellular vesicle-based photo-assisted therapeutic platforms from passive drug carriers to engineered biomimetic systems integrating multiple biological and therapeutic functions. We first discuss the transition from synthetic nanocarriers to extracellular vesicles and summarize the biological properties that distinguish these natural nanocarriers from conventional delivery systems. We then analyze current engineering strategies for optimizing therapeutic cargo loading and programming the extracellular vesicle biological interface through chemical, genetic, and biomimetic approaches that enhance tumor targeting, intracellular trafficking, and communication with the tumor microenvironment. Building upon these advances, we propose a functional framework describing the progressive evolution of extracellular vesicle-based photo-assisted platforms from targeted delivery systems to multifunctional nanotherapeutics integrating immune modulation, ferroptosis induction, metabolic reprogramming, hypoxia alleviation, image-guided therapy, and theranostic and image-guided capabilities. Finally, we discuss the major biological, technological, manufacturing, and regulatory barriers that currently limit clinical translation and highlight emerging opportunities for developing engineered extracellular vesicles capable of sensing, communicating with, and dynamically remodeling the tumor ecosystem. Together, this review provides a critical overview of current developments in EV-based photo-assisted cancer therapy, distinguishing experimentally demonstrated engineering strategies from emerging concepts whose translational feasibility remains to be established. Despite these advances, EV-based photo-assisted therapeutic platforms remain at the preclinical stage, with no clinical trials yet evaluating their therapeutic use in humans.

Keywords:  biomimetic drug delivery; extracellular vesicles; photo-assisted therapy; photodynamic therapy; theranostics; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1955178
Biomaterials. 2026 Sep 30. pii: S0142-9612(26)00698-8. [Epub ahead of print]338(Pt A): 124674

Engineering extracellular vesicles for multi-cargo co-delivery in silicosis and related fibrotic diseases: design strategies and translational prospects.

Zhen Chen, Yuqin Liu, Shuo Yang, Yanhong Lai, Hong Zhang, Kaiji Lang, Wenzhen Li, Xinyuan Zhao, Weihong Chen, Dongming Wang.

  Silicosis remains therapeutically intractable because its three driver axes-the NLRP3 inflammasome, ROS/Nrf2 oxidative stress, and TGF-β/Smad fibrosis-interlock into a self-reinforcing network whose topological redundancy reroutes signalling around any single-target drug, the structural basis for repeated single-agent failure. Existing nanocarriers cannot meet the resulting demand for multi-cargo delivery: lipid nanoparticles risk triggering NLRP3, polymeric carriers escape endosomes too poorly to deliver nucleic acids, and inorganic particles intensify the ROS-driven fibrotic loop. Engineered exosomes close this gap. Their native architecture matches the silicotic microenvironment and can carry nucleic acids, proteins, and small molecules together at defined ratios across the vesicle population, while surface CD47 can confer immune evasion, donor-encoded integrins can direct cell-selective pulmonary tropism, and membrane fusion can deliver payloads directly into the cytoplasm, - properties we argue must be demonstrated for each engineered construct rather than assumed. Here, we evaluate the complete engineering pipeline - donor-cell selection, GMP-compatible isolation, cargo loading by electroporation and bio-orthogonal surface click chemistry, and stimuli-responsive release whose triggering thresholds have been established in oncological rather than fibrotic settings and require validation in silicosis. Preclinical evidence, graded by a three-tier scheme, is consistent with coordinated multi-axis efficacy spanning NLRP3 suppression, Nrf2 restoration, and TGF-β/Smad blockade, but remains predominantly Grade B and C; we critically appraise manufacturing scalability, co-loading optimization, and endotype-matched dosing as the milestones still separating this platform from clinical deployment.

Keywords:  Engineered exosomes; Multi-cargo co-delivery; Pathological network topology; Pulmonary fibrosis; Targeted drug delivery

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124674
Avicenna J Med Biotechnol. 2026 Jul-Sep;18(3):18(3): 189-206

Engineered Extracellular Vesicles for Cartilage Regeneration: Bridging Biological Complexity to Clinical Precision.

Shayan Boozarjomehri Amnieh, Sina Mahmoudian, Mahdi Ghorbani, Javad Behroozi, Ali Shakerimoghaddam, Seyyed Morteza Tabatabaei, Zahra Hami, Mohsen Chamanara, Reza Heidari.

  Osteoarthritis (OA) is a common degenerative joint disease characterized by pain, stiffness, progressive cartilage loss, and reduced mobility. Current treatments primarily aim to relieve symptoms rather than restore damaged cartilage, and durable regeneration of native hyaline cartilage remains a major clinical challenge. Extracellular Vesicles (EVs), particularly those derived from Mesenchymal Stem Cells (MSCs), have emerged as promising cell-free therapeutic platforms because of their ability to modulate inflammation, regulate chondrocyte activity, and influence extracellular matrix metabolism. However, EV heterogeneity, source-dependent variability, limited targeting efficiency, inconsistent cargo loading, and lack of standardized manufacturing protocols continue to restrict their clinical translation. This review summarizes recent advances in engineered EV-based strategies for OA and cartilage repair, including parental-cell preconditioning, genetic modification, surface functionalization, cargo loading, artificial EV platforms, and biomaterial-assisted delivery. Importantly, we distinguish between in vitro findings, preclinical animal studies, and early clinical evidence to provide a balanced assessment of translational readiness. We also discuss key regulatory and safety challenges, including GMP-compliant production, batch-to-batch variability, quality-control criteria, potency assays, scalability, biodistribution, and long-term safety. By integrating EV engineering with translational and regulatory perspectives, this review highlights the potential of engineered EVs as future disease-modifying tools for OA while emphasizing that their clinical efficacy and capacity to restore durable hyaline cartilage remain to be demonstrated in robust human studies.

Keywords:  Bioengineering; Clinical translation; Engineered EVs; Extracellular vesicles; Osteoarthritis; Regenerative medicine; Stem cells

DOI:  https://doi.org/10.18502/ajmb.v18i3.22236
Mol Neurobiol. 2026 Oct 07. pii: 954. [Epub ahead of print]63(1):

Advances in Extracellular Vesicle-Based Innovative Drugs Targeting Alzheimer's Disease.

Shangfeng Liu, Jueqin Lu, Jiaxin Liu, Huaxiang Liu, Zhongliang Liu, Danjing Yang, Xingqun Liang, Jun Xu.

  The scarcity of effective therapies for Alzheimer's disease (AD) underscores the urgent need for innovative strategies. This review focuses on the targeted delivery of engineered small extracellular vesicles (sEVs, 30-150 nm). By capitalizing on their intrinsic properties as natural nanocarriers-including low immunogenicity and excellent biocompatibility-these EVs can be engineered to co-deliver therapeutic cargoes such as specific miRNAs, neurotrophic factors (e.g., BDNF), and nucleic acid modalities (e.g., siRNA/ASO targeting BACE1). While a single construct simultaneously delivering all these agents with proven in vivo synergy remains a conceptual framework rather than a validated reality, independent studies have demonstrated that EV-mediated delivery of each cargo type exerts beneficial effects on AD pathology, including Aβ clearance, Tau pathology alleviation, and neuroinflammation suppression. The intranasal administration offers a significant brain-targeting advantage by enabling direct nose-to-brain delivery, bypassing the blood-brain barrier and minimizing peripheral biodistribution. Recently, a phase I/II trial (Ruijin Hospital) demonstrated that intranasal MSC-EVs are safe and produce durable cognitive improvements (ADAS-Cog ↓ 2.33 points at week 12, sustained to - 3.98 points at week 36) in the medium-dose cohort, exceeding the minimal clinically important difference (MCID) of ≥ 2 points for AD. Based on these demonstrated clinical and preclinical evidence, we propose that rationally engineered EVs, following rigorous systematic pharmacology and safety assessments, hold transformative potential to pioneer a safe, efficacious, and non-invasive breakthrough therapy for AD, while acknowledging that critical challenges in GMP manufacturing, biodistribution, and regulatory approval remain to be resolved.

Keywords:  Alzheimer’s disease (AD); Blood-brain barrier (BBB); Extracellular vesicles (EVs); Intranasal delivery

DOI:  https://doi.org/10.1007/s12035-026-06223-x
Transl Res. 2026 Oct 03. pii: S1931-5244(26)00211-2. [Epub ahead of print]298 85-98

Coupling extracellular vesicles with nanomedicine for precision theranostics.

Tehreem Kausar, Waqas Ahmed, Tayyab Shafiq, Robina Kausar, Yujie Liang, Li Duan.

  Nanomedicine represents one of the pivotal technologies that further bridges critical gaps in precision theranostics through targeted delivery, integrated diagnostics and therapeutics, and personalized treatment. Among various nanocarriers, extracellular vesicles (EVs) have attracted substantial interest owing to their nanoscale dimensions, favorable biocompatibility relative to synthetic counterparts, and innate capacity to transport bioactive cargoes. The central focus in this field is the inherent heterogeneity of EVs, which provides promising opportunities for biomarker-driven patient stratification while presents significant challenges in quality control and batch reproducibility. Recent progress in surface engineering has significantly optimized the targeting capability and pharmacokinetic profiles of EV-based systems in preclinical models, yet their clinical translation remains restricted by major challenges, including manufacturing scalability and the lack of disease and subgroup-specific standardization. Given that EV functionality and safety are highly context-dependent varying with cell source, loading strategy, and recipient pathophysiology bridging the gap between large-scale production and patient-specific customization emerges as a critical priority for translating EV-based nanomedicines into routine precision oncology treatment and beyond.

Keywords:  Clinical translation; Extracellular vesicles; Precision theranostics; Standardization; Surface modification; Therapeutic cargo delivery

DOI:  https://doi.org/10.1016/j.trsl.2026.10.001
Front Pharmacol. 2026 ;17 1930673

Recent advances in research on novel therapeutic mechanisms and strategies for exosome-based treatment of ischemic stroke.

Tairan Liu, Hanlin Cao, Xi Chen, Jiaxin Huang, Qiao Zhang, Mingze Sun, Wen Zeng, Yu Su.

  Ischemic stroke (IS) accounts for over 80% of all stroke cases, featuring high disability, mortality, and recurrence rates. Conventional intravenous thrombolysis and mechanical thrombectomy are limited by narrow therapeutic windows, reperfusion injury, and the blood-brain barrier (BBB), which impedes the entry of neuroprotective agents into the brain parenchyma. Exosomes (Exos) are cell-secreted nanoscale extracellular vesicles (EVs) that carry miRNAs, proteins, and lipids, with low immunogenicity, BBB permeability, and ease of genetic modification, making them promising cell-free therapeutic agents for central nervous system (CNS) disorders. Exos alleviate cerebral ischemia-reperfusion injury by suppressing multiple forms of programmed cell death, oxidative stress, and neuroinflammation, repairing the BBB, and facilitating angiogenesis and neurogenesis. Genetic engineering, surface peptide modification, and drug loading further enhance brain-targeted exosomal enrichment. This review systematically summarises Exos biogenesis, multi-pathway neural repair mechanisms mediated by exosomal miRNAs, engineered delivery strategies, translational bottlenecks, and future research directions, aiming to provide theoretical support for the clinical transformation of Exos therapy for IS.

Keywords:  blood–brain barrier; cerebral ischemia-reperfusion injury; engineered exosomes; exosomes; ischemic stroke; mesenchymal stem cells; miRNA; targeted delivery

DOI:  https://doi.org/10.3389/fphar.2026.1930673
J Control Release. 2026 Oct 07. pii: S0168-3659(26)00846-1. [Epub ahead of print] 115442

Metabolically engineered chimeric probiotic-cancer vesicles orchestrate anti-tumor systemic immunity.

Van Hieu Duong, Van Dat Bui, Torsha Ghosh, Jeongyun Kim, Won Ho Jang, Sol Shin, Chan Ho Kim, Um Wooram, Sohyun Cho, Chaemin Lee, Chan-Hwa Chung, Soyoung Son, Jae Hyung Park.

  The paradigm shift toward patient-centric precision medicine has established personalized cancer vaccines (PCVs) as a key strategy for eliciting tumor-selective immunity. However, traditional cell-based PCVs face significant translational barriers, including manufacturing complexity and safety concerns. While tumor-derived extracellular vesicles (TDEVs) offer a promising cell-free alternative that recapitulates the parental tumor's antigenic landscape, their therapeutic efficacy is frequently antagonized by intrinsic immunosuppressive cargo. Here, we report ChimeraVax, a chimeric vesicular vaccine platform engineered by covalently conjugating TDEVs with Lactobacillus acidophilus-derived membrane vesicles (LAMVs) via bio-orthogonal, copper-free click chemistry. In this hybrid assembly, the TDEVs serve as a comprehensive antigen reservoir, while the LAMVs provide potent natural adjuvanticity that bypasses TDEV-mediated immunosuppression. In vitro, ChimeraVax facilitated the synchronized delivery of tumor antigens and immunostimulatory molecules to dendritic cells, significantly enhancing antigen uptake and pro-inflammatory signaling. In a murine model of aggressive triple-negative breast cancer, subcutaneous administration of ChimeraVax coordinated both innate and adaptive immune responses, yielding robust antitumor efficacy. Notably, ChimeraVax showed strict antigen dependence, selectively suppressing matched lesions with minimal effects on mismatched tumors, highlighting its specificity and translational potential as a modular personalized cancer vaccine platform.

Keywords:  Antigen-adjuvant co-delivery; Cancer vaccine; Chimera vesicles; Metabolic engineering

DOI:  https://doi.org/10.1016/j.jconrel.2026.115442
J Am Soc Nephrol. 2026 Oct 08.

Fibroblastic Reticular Cell-Derived and CD5L-Enriched Exosomes Remodel Renal Lipid Metabolism in Porcine Sepsis-Associated Acute Kidney Injury.

Yiming Li, Wen Wu, Dongxue Xu, Pan Zhai, Chang Hu, Jinmeng Suo, Yusheng Chen, Xiaoyu Zhang, Xiang Zhou, Xiaocheng Weng, Timothy R Billiar, John A Kellum, Jing Wang, Bo Hu, Zhiyong Peng.

BACKGROUND: Sepsis-associated AKI is a life-threatening condition associated with profound metabolic dysfunction, including impaired mitochondrial fatty acid handling. Therapies capable of reversing this metabolic dysfunction remain lacking. Using a clinically relevant porcine model, we investigated whether kidney-targeted fibroblastic reticular cell-derived and CD5L-enriched exosomes could ameliorate sepsis-associated AKI.
METHODS: We generated engineered exosomes derived from fibroblastic reticular cells or CD5L-overexpressing cells and functionalized them with the kidney-targeting LTH peptide. Therapeutic efficacy and safety were evaluated in a porcine model of lipopolysaccharide-induced sepsis-associated AKI. Integrated multiomic and cellular analyses were performed to examine the associated molecular pathways.
RESULTS: In septic pigs, both fibroblastic reticular cell-derived and CD5L-enriched exosomes improved systemic hemodynamics, renal microvascular perfusion, and kidney injury indices. Exosome treatment reduced renal lipid-droplet and acylcarnitine accumulation. CD5L interacted with fatty acid synthase, and treatment was associated with changes in short-chain fatty acids and AMPK-ACC-CPT1A signaling. These lipid-metabolic changes were accompanied by improved mitochondrial bioenergetic indices, preserved mitochondrial morphology, and reduced markers of tubular cell pyroptosis.
CONCLUSIONS: Kidney-targeted fibroblastic reticular cell-derived and CD5L-enriched exosomes produced comparable improvements in kidney injury indices and were associated with renal lipid-metabolic and mitochondrial remodeling in a large-animal model of sepsis-associated AKI.

DOI: https://doi.org/10.1681/ASN.0000001266
Adv Mater. 2026 Oct 10. e75362

Artificial Regulatory T Cells Orchestrate Phase-Spanning Regeneration in Refractory Tissue Injuries.

Bo Li, Jiale Li, Guowei Zhang, Cheng Li, Denghui Xie, Jun Deng.

  Regulatory T cells (Tregs) possess potent multiphasic reparative capacity; however, their application is limited by ethical and regulatory challenges associated with live cell therapies. Treg-derived exosomes (TExo) exhibit low immunogenicity while enriching regenerative signaling relative to parental Tregs. Current exosome carriers place greater emphasis on sustained release than on factors affecting vesicle stability, such as nonspecific interactions and confinement effects. Inspired by the multivesicular body (MVB), we engineered artificial Tregs (ATregs) with an MVB-like architecture that integrates vesicle protection with sustained release through a reconstructed storage microenvironment. This design enables phase-aligned TExo release and extends functional activity by more than an order of magnitude compared with free TExo. ATregs sequentially coordinate the suppression of inflammation, enhancement of angiogenesis, and stimulation of skin appendage regeneration. In diabetic wounds and deep second-degree burn models, which represent intrinsic repair dysfunction and severe structural tissue loss, ATregs markedly accelerate healing and outperform conventional strategies across murine and porcine models. These findings overcome the key limitations of exosome therapies and open a new avenue for next-generation regenerative therapeutics.

Keywords:  artificial regulatory T cells; exosome protection; tissue regeneration; treg‐derived exosomes

DOI:  https://doi.org/10.1002/adma.75362
Med Oncol. 2026 Oct 08. pii: 318. [Epub ahead of print]43(11):

Engineered mesenchymal stem cell-derived small extracellular vesicles delivering miR-124 suppress colorectal cancer progression through EZH2 downregulation and attenuation of STAT3 signaling.

Roudabeh Behzadi Andouhjerdi, Fatemeh Hosseini, Niki Hosseinzadeh, Sakineh Zivari, Shokoufeh Salkhordeh, Marzieh Mohammadi, Maryam Rahmani, Parmida Hatami, Shima Sadat Naji, Mohammad Pourtahmasebi, Mina Khanabadi, Mahtab Golbahar, Arezoo Hajesmaeili, Parisa Eftekhari, Mohadeseh Asbaghi, Ali Norouz-Nejad, Parastoo Akbarabadi, Mohammad H Ghazimoradi, Sadegh Babashah, Zeinab Piravar.

  Colorectal cancer (CRC) progression is driven by dysregulated molecular pathways and epigenetic alterations, including enhancer of zeste homolog 2 (EZH2)-mediated histone methylation and STAT3 hyperactivation. While microRNA-124 (miR-124) acts as a tumor suppressor by targeting EZH2, its clinical translation is hindered by delivery challenges. Here, we engineered mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) to deliver miR-124, exploiting their tumor-homing capacity and biocompatibility to suppress CRC progression. Bioinformatic analysis of clinical datasets revealed miR-124 downregulation in CRC tissues, correlating with advanced stages and poor prognosis. Lentiviral transduction enabled efficient miR-124 packaging into MSC-sEVs, which were internalized by CRC cells, restoring functional miR-124 levels. Mechanistically, miR-124 directly silenced EZH2, thereby suppressing its oncogenic activity. This led to attenuated STAT3 phosphorylation-a dual effect that inhibited proliferation, migration, and epithelial-mesenchymal transition (EMT) in CRC cells. In vitro, MSC-sEV-miR-124 induced apoptosis, sensitized cells to 5-fluorouracil, and reversed chemoresistance via EZH2 downregulation. In vivo, MSC-sEV-miR-124 significantly reduced tumor growth in BALB/c mice, downregulated EZH2/STAT3 signaling, and suppressed Ki-67 and EMT markers in xenografts. This study provides proof-of-concept that engineered MSC-sEVs can serve as a delivery platform for miR-124 in murine CRC models, offering a dual-targeting strategy against EZH2 and STAT3 to disrupt CRC progression. Our findings suggest that EV-based miRNA delivery warrants further investigation as a strategy to modulate the tumor microenvironment, providing a foundation for development aimed at overcoming epigenetic and oncogenic signaling barriers in CRC therapy.

Keywords:  Colorectal cancer; EZH2; Mesenchymal stem cells; Small extracellular vesicles; miR-124-3p

DOI:  https://doi.org/10.1007/s12032-026-03418-z
Front Bioeng Biotechnol. 2026 ;14 1966076

Engineered mesenchymal stem cell-derived extracellular vesicles as programmable biomaterial platforms for liver fibrosis: design principles, manufacturing and clinical translation.

Fanghong Wang, Kexiang Zhu, Xiaoliang Zhu, Jia Yao, Zongbin Sun, Xun Li.

  Liver fibrosis remains a major unmet clinical challenge characterized by persistent activation of hepatic stellate cells (HSCs), chronic inflammatory remodeling, and impaired hepatocyte regeneration. Although mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutics, native EVs are limited by insufficient target specificity, rapid systemic clearance, heterogeneous cargo composition, and poorly defined dose-response relationships, thereby constraining their translational potential. Recent advances in bioengineering have redefined MSC-EVs as programmable nanobiomaterial platforms rather than passive biological byproducts. Through multilevel engineering, including parent cell modification, cargo modulation, surface functionalization, and biomaterial-assisted delivery, MSC-EVs can be rationally designed to modulate key fibrogenic pathways, reprogram immune microenvironments, restore extracellular matrix homeostasis, and enhance hepatocyte regeneration. Concurrently, innovations in scalable three-dimensional bioprocessing, good manufacturing practice-compatible purification, and mechanism-linked potency assays are accelerating the transition of engineered EVs toward clinically viable products. This review integrates pathophysiological targeting with multilevel engineering strategies, with particular emphasis on nano-bio interface design, quality-by-design manufacturing, critical quality attribute definition, and key translational considerations, including dosing, safety, and regulatory frameworks. By positioning engineered MSC-EVs as precision biomaterial systems with controllable composition, programmable functionality, and tunable pharmacokinetics, we propose a rational design paradigm that bridges biological efficacy with scalable manufacturing and regulatory readiness. Collectively, such engineering integration is poised to transform EV-based antifibrotic therapy from experimental promise into clinically actionable intervention.

Keywords:  biomaterial platforms; engineering integration; mechanism-linked potency; nano-bio interface; quality-by-design; translational robustness

DOI:  https://doi.org/10.3389/fbioe.2026.1966076
STAR Protoc. 2026 Oct 08. pii: S2666-1667(26)00544-7. [Epub ahead of print]7(4): 104891

Protocol for scalable production of orally deliverable R-spondin1-loaded small extracellular vesicles for WNT-signaling activation and tissue regeneration.

Lingyan Yang, Ting Jiang, Shixiang Wang, Yue Yang, Zhiping Qiao, Yun-Shen Chan.

  R-spondin1 plays a pivotal role in potentiating canonical WNT/β-catenin signaling, a pathway critical for maintaining stem cell homeostasis and driving tissue regeneration. Here, we present a scalable, serum-free protocol for producing R-spondin1-loaded small extracellular vesicles (evRSPO1) from engineered HEK293 cells, with multimodal characterization of vesicle quality and bioactivity. We also describe steps for in vitro functional validation of the vesicles using mouse intestinal organoids and for in vivo therapeutic applications in mouse intestinal regeneration via oral delivery. For complete details on the use and execution of this protocol, please refer to Yang et al.1,2.

Keywords:  Organoids; Stem Cells; Tissue Engineering

DOI:  https://doi.org/10.1016/j.xpro.2026.104891
Small. 2026 Oct 05. e75973

Rapid and Efficient Affinity Isolation of Engineered Extracellular Vesicles Encapsulating Functional Proteins via Internal Twin-Strep Tetraspanin Tagging.

Minh-Tu Pham, Jona Benjamin Krohn, Janis Meyer, Christian Ritter, Martin Schneider, Dominic Helm, Dario Frey, Kleopatra Rapti, Uta Haselmann-Weiss, Elif Toprak, Viet Loan Dao Thi, Florian Leuschner, Dirk Grimm, Karl Rohr, Ralf Bartenschlager.

  Extracellular vesicles (EVs) are mediators of intercellular communication and promising protein-delivery vehicles, but isolation of sufficiently pure, intact, engineered EVs remains challenging due to abundant cellular and serum-derived contaminants. Here, structure-guided engineering of the canonical EV tetraspanins, CD63 and CD9, is applied. Permissive sites for the internal insertion of the twin-Strep tag are identified within unstructured regions of their large extracellular loops, using flexible linkers. This design preserves scaffold functionality and enables efficient antibody-free affinity isolation of intact EVs using Strep technology. Fusing proteins of interest (POIs) to the C-terminus of these scaffolds, either directly or via the photocleavable protein PhoCl2, enables efficient luminal POI loading with optional optogenetic control of POI release. Proteomic analysis confirms high purity of isolated EVs with more than 96% of contaminants removed, allowing sensitive detection of possibly novel EV-associated proteins. Additionally, this approach effectively removes hepatitis C virus, which has EV-like biophysical properties, and adeno-associated virus, demonstrating high specificity. Vesicular stomatitis virus glycoprotein coating of EVs facilitates endosomal escape, while PhoCl2 cleavage enables POI release after EV uptake by target cells, including primary human hepatocytes and hepatocyte-like cells. This strategy provides a broadly applicable platform for producing intact, pure engineered EVs for basic and translational studies.

Keywords:  EV‐mediated delivery; affinity isolation; intact engineered EVs; photocleavable protein; protein‐of‐interest; twin‐Strep‐tagged CD63/CD9; virus contamination

DOI:  https://doi.org/10.1002/smll.75973
Bioeng Transl Med. 2026 Sep;11(5): e70150

Innovative myeloid ecotropic viral integration site 1-engineered exosome platform combating oxidative stress and inflammation in acute pulmonary damage.

Yukun Zhang, Ke Pang, Zefa Ling, Shouyong Wang, Bo Hu, Surong Deng, Zhao Yang.

  Phosgene-induced acute lung injury (P-ALI) remains a severe clinical challenge due to the absence of targeted therapies. In this study, we developed a novel therapeutic strategy based on myeloid ecotropic viral integration site 1-engineered exosomes loaded with curcumin (Meis1-Exo@Cur). This nanotherapeutic platform exhibited potent protective effects in both cellular and animal models of P-ALI, significantly reducing inflammation, oxidative stress, and apoptosis while promoting tissue repair. Mechanistically, Meis1-Exo@Cur exerted its therapeutic effects through coordinated inhibition of the nuclear factor kappa-B/mitogen-activated protein kinase signaling pathways and activation of the Nrf2/HO-1 pathway, accompanied by remodeling of the immune microenvironment. These findings identify Meis1-Exo@Cur as a promising therapeutic candidate for P-ALI and provide a potential framework for exosome-based precision therapy in inflammatory lung diseases.

Keywords:  Meis1; acute lung injury; curcumin; exosome engineering; oxidative stress

DOI:  https://doi.org/10.1002/btm2.70150
Colloids Surf B Biointerfaces. 2026 Oct 06. pii: S0927-7765(26)00822-2. [Epub ahead of print]270 116234

Curcumin-loaded pH-responsive hybrid nanovesicles from Bergenia purpurascens root exosomes for synergistic lung cancer treatment.

Xiang Xu, Jinying Gu, Jia Zhang, Tong Wang, Yirui Zhang, Yanjie Ding, Xiaoting Zhang, Xiaoting Wang, Ying Xu, Nannan Liu, Keran Li, Liuyao Xie, Xiaohe Li, Zhun Bi, Xueren Li, Honggang Zhou, Dongjie Wang, Xiaoting Gu, Xiaoyu Ai, Cheng Yang.

  Lung cancer, with its high incidence and mortality rates, urgently demands innovative therapeutic strategies to address the limitations of conventional treatments, such as nonspecific toxicity and the development of drug resistance. Plant-derived exosomes have recently emerged as promising natural nanocarriers, owing to their inherent biocompatibility, low immunogenicity, and intrinsic bioactive properties. In this work, a novel hybrid nanovesicle system (HNVs) was developed by fusing exosomes isolated from Bergenia purpurascens roots (BPR-Exos), which inherently inhibit tumor migration through the ID1-Snail pathway, with pH-sensitive liposomes. This design integrated the biological activity of BPR-Exos with the engineered capability of tumor-acid-responsive drug release. Upon encapsulation of the anticancer drug curcumin (Cur), HNVs@Cur demonstrated high encapsulation efficiency, potentiated cellular uptake, and sustained release. Both in vitro and in vivo studies showed that HNVs@Cur significantly suppressed the proliferation, migration, invasion of lung cancer cells, and inducing apoptosis. Furthermore, HNVs@Cur exhibited favorable tumor-targeting ability and biosafety. Taken together, this novel hybrid nanovesicle system represents a promising synergistic strategy for targeted lung cancer therapy, providing a valuable reference for further therapeutic development.

Keywords:  Bergenia purpurascensroot exosomes; Curcumin; Hybrid nanovesicle systems; ID1-Snail pathway; Lung cancer

DOI:  https://doi.org/10.1016/j.colsurfb.2026.116234
Exp Gerontol. 2026 Oct 08. pii: S0531-5565(26)00331-1. [Epub ahead of print] 113352

Synergistic reversal of mesenchymal stem cell senescence by engineered exosomal delivery of a dual miR-195/miR-188 sponge.

Faranak Elmi, Arezou Azizsoltanti, Mohammad Taghizadeh, Mohammad Reza Baghaban Eslaminejad, Effat Alizadeh.

   BACKGROUND: Cellular senescence critically impairs the regenerative potential and therapeutic efficacy of adipose-derived mesenchymal stem cells (AD-MSCs). MicroRNAs miR-195 and miR-188 are key regulators of aging-associated pathways, making them attractive nucleic acid targets for senescence modulation. In this study, exosomes derived from Wharton's jelly mesenchymal stem cells (WJ-MSCs) were engineered to deliver a dual miR-195/miR-188 sponge.
METHODS: Quantitative RT-PCR analysis confirmed that sponge-loaded exosomes significantly reduced intracellular levels of miR-195 and miR-188, demonstrating effective functional sequestration. Exosomes were characterized by dynamic light scattering, electron microscopy, and western blotting. Functional assays demonstrated efficient intracellular delivery and a robust reversal of senescence-associated phenotypes in replicative senescent AD-MSCs.
RESULTS: Treatment significantly reduced senescence markers, including p16, p53, NF-κB, IL-6, and RB, while decreasing reactive oxygen species levels and β-galactosidase activity. Suppression of miR-195/miR-188 was associated with the restoration of the telomere length and reactivation of stemness-associated genes (SOX2, OCT4), suggesting modulation of telomere maintenance and cell-cycle regulatory pathways, including p53-RB signaling. Clonogenic capacity and cellular viability were markedly enhanced.
CONCLUSION: In conclusion, exosome-mediated delivery of a dual miRNA sponge represents a mechanism-driven strategy to reprogram senescence-associated gene networks and restore MSC function. This approach provides a promising cell-free nucleic acid therapeutic platform for regenerative medicine applications.

Keywords:  Adipose derived mesenchymal stem cells; Exosomes; Senescence; Wharton's jelly mesenchymal stem cells; miR-195/miR-188 sponge

DOI:  https://doi.org/10.1016/j.exger.2026.113352
Int J Nanomedicine. 2026 ;21 636187

Engineered Source-Specific Extracellular Vesicles for Neurodegenerative Diseases: From Biological Barriers to Targeted Delivery Strategies.

Hanglu Li, Shuangyan Jiang, Xinyi Liu, Jingting Zhang, Ye Hu, Bo Liu, Min Wu, Huaqiong Li, Bo Li.

  With the rapidly aging global population, neurodegenerative diseases (NDDs) present an escalating challenge to public health. The complex, self-perpetuating pathological network of NDDs, encompassing aberrant protein aggregation, chronic neuroinflammation, synaptic impairment, and mitochondrial dysfunction, significantly impedes the efficacy of traditional single-target pharmacological interventions. Extracellular vesicles (EVs), which encapsulate a diverse array of functional cargoes, including proteins, lipids, and nucleic acids, mediate both horizontal intercellular communication and cross-kingdom signaling. Their distinctive biological properties-characterized by low immunogenicity, favorable biocompatibility, and an intrinsic ability to cross the blood-brain barrier (BBB)-position EVs as a promising multi-target pharmacological platform for treatment of NDDs. By integrating genetic, chemical, and physical engineering strategies, these vesicles have been redefined as programmable nanotherapeutic tools. To address the cost and scalability constraints associated with mammalian cell-derived EVs, plant-derived EV-like nanoparticles (PDENs) represent a promising "green" platform. In this review, we systematically delineate the pathological mechanisms of NDDs, the diverse sources and characteristics of EVs, their functionalization via advanced engineering, and their multifaceted applications in NDDs therapy. Finally, we discuss the translational potential of these platforms, particularly their capacity to address the challenges associated with BBB penetration, and outline a framework to guide the development and clinical evaluation of EV-based therapies for NDDs.

Keywords:  PDENs; blood-brain barrier; extracellular vesicles; nanomedicine; neurodegenerative diseases; plant-derived EV-like nanoparticles

DOI:  https://doi.org/10.2147/IJN.S636187