bims-engexo Biomed News
on Engineered exosomes
Issue of 2026–09–27
twelve papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur



  1. Nanomedicine. 2026 Sep 25. pii: S1549-9634(26)00129-2. [Epub ahead of print] 103028
      The pathological complexity of Alzheimer's disease (AD) necessitates multifaceted therapeutic strategies. By integrating single-nucleus RNA sequencing analysis of 143,214 nuclei, this study identified excitatory neurons as the pivotal locus of cellular damage, manifesting significant dysregulation of pathways associated with proteostasis and autophagy. To counteract these cellular deficits, we developed a neuron-centric targeting strategy utilizing neural stem cell-derived exosomes engineered to overexpress the scaffolding protein Arc (Arc-exo). Following intranasal administration, Arc-exo demonstrated efficient central nervous system accumulation and achieved precision delivery by leveraging the intrinsic neurorestorative properties of the Arc protein and its specific affinity for neurons. Experimental results demonstrated that Arc-exo significantly alleviated AD pathological symptoms by reducing β-amyloid deposition, suppressing neuroinflammation, and repairing neuronal damage. Further mechanistic investigation revealed that Arc-exo restored cellular homeostasis by inhibiting the mTOR signaling pathway and reactivating autophagy. This study highlights engineered exosomes as efficient nanoplatforms for precision therapy in neurodegenerative diseases.
    Keywords:  Alzheimer's disease; Arc; Engineered exosomes; Intranasal delivery; Neural stem cells
    DOI:  https://doi.org/10.1016/j.nano.2026.103028
  2. J Diabetes Investig. 2026 Sep 26.
       BACKGROUND: Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus. The specific role of M1 macrophage-derived exosomes in DN progression remains largely unexplored.
    METHODS: THP-1 monocytes were differentiated into M0 macrophages and polarized into M1 macrophages for exosome extraction. WTAP was silenced using shRNA to generate WTAP-deficient exosomes. Glomerular endothelial cells (GECs) were exposed to high glucose (HG) and co-incubated with modified exosomes. Cell viability, oxidative stress, apoptosis, barrier function, and angiogenic capacity were assessed. The WTAP-S1PR2 interaction was validated by RIP, MeRIP, and dual-luciferase assays. In vivo, db/db mice received tail vein injections of respective exosomes for 8 weeks, followed by assessments of renal function, histopathology, and inflammation.
    RESULTS: M1 exosomes were internalized by GECs. WTAP delivered by shNC/M1-Exo bound S1PR2 mRNA, enhancing its m6A modification and stability, thereby activating the RhoA/ROCK1 axis and aggravating HG-induced GEC injury, oxidative stress, apoptosis, and endothelial permeability. Conversely, shWTAP/M1-Exo attenuated these effects, and S1PR2 overexpression reversed the protective effects. In vivo, shWTAP/M1-Exo improved renal function, ameliorated histopathological damage and fibrosis, and reduced systemic inflammation in db/db mice.
    CONCLUSION: M1 macrophage-derived exosomes promote DN progression by delivering WTAP to stabilize S1PR2 mRNA in an m6A-dependent manner. Engineered exosomes lacking WTAP represent a promising targeted nanomedicine strategy for DN treatment.
    Keywords:  Diabetic nephropathy; M1 macrophages; exosomes
    DOI:  https://doi.org/10.1111/jdi.70446
  3. Drug Deliv. 2026 Dec 31. 33(1): 2728215
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors due to its dense desmoplastic stroma, poor vascular perfusion, and the limited intratumoral delivery of chemotherapeutic agents such as oxaliplatin (OXA). Extracellular vesicles (EVs) offer a biocompatible platform for drug delivery, yet their intrinsic lack of tumor specificity constrains therapeutic efficacy. Ephrin type-A receptor 2 (EphA2), which is highly expressed and efficiently internalized in PDAC, represents an attractive molecular target for guiding EVs into tumor cells. In this study, we engineered HEK293T-derived EVs to display membrane-anchored anti-EphA2 Fab fragments and encapsulate OXA (EVs-EphA2/OXA) as a targeted delivery system for PDAC therapy. Stable producer cells expressed the engineered Fab on the plasma membrane and released vesicles that retained canonical EV markers and robust antigen-binding capability. EVs-EphA2 demonstrated selective uptake into EphA2-positive AsPC-1 and BxPC-3 cells and induced significantly greater cytotoxicity than free OXA or untargeted EVs/OXA in vitro. In xenograft models, EVs-EphA2/OXA achieved the most pronounced tumor suppression, accompanied by increased γH2AX-associated DNA damage, enhanced TUNEL-positive apoptosis, and preferential tumor accumulation in biodistribution imaging. These findings demonstrate that EphA2-targeted EVs can substantially improve intratumoral delivery of OXA and amplify antitumor efficacy, supporting EVs-EphA2/OXA as a promising platform for receptor-guided chemotherapy in PDAC.
    Keywords:  EphA2; Extracellular vesicles; oxaliplatin; pancreatic ductal adenocarcinoma; targeted drug delivery
    DOI:  https://doi.org/10.1080/10717544.2026.2728215
  4. J Drug Target. 2026 Sep 24. 1-19
       BACKGROUND: Conventional therapies for myocardial infarction (MI) have limited efficacy in restoring cardiac function. This study aimed to construct a novel engineered exosome platform for promoting post-MI cardiac regeneration and evaluate its therapeutic efficacy.
    METHODS: CCK-8 assays, flow cytometry, and western blotting were employed to evaluate the effects of DOPE-CHP-exosome on cardiomyocyte proliferation and apoptosis. The in vivo distribution of DOPE-CHP-exosome was assessed by fluorescence imaging, frozen sectioning, and DiI tracing. Cardiac function was evaluated using echocardiography, Masson's trichrome staining, and Sirius Red staining.
    RESULTS: The novel DOPE-CHP-exosome functionalized with cardiac homing peptide (CHP) and loaded with miR-126, miR-145, or miR-340-5p (DOPE-CHP-miR) enhanced exosome uptake by cardiomyocytes, improved cell viability, and reduced apoptosis in H2O2-induced primary cardiomyocyte injury models. In vivo, these exosomes markedly improved left ventricular contractility in MI mice, as evidenced by increased LVEF and LVFS and decreased LVEDV and LVESV. Additionally, the expression levels of CD31 and Ki67, markers of angiogenesis and proliferation, were significantly elevated. Notably, DOPE-CHP-miR-126 exhibited the most pronounced therapeutic effects.
    CONCLUSIONS: These DOPE-CHP-exosome alleviate MI and improve cardiac function by promoting cardiomyocyte viability and angiogenesis while inhibiting apoptosis.
    Keywords:  CHP; angiogenesis; engineered exosome; miRNA; myocardial infarction
    DOI:  https://doi.org/10.1080/1061186X.2026.2687010
  5. Pharmaceutics. 2026 Aug 26. pii: 1062. [Epub ahead of print]18(9):
      The biological fate of lipid-based nanocarriers (LBNs) is shaped at the interface. Whereas core architecture governs cargo loading, protection, and baseline release, surface architecture mediates the carrier's initial interactions with proteins, cells, extracellular matrices, and tissue barriers, thereby influencing colloidal stability, immune recognition, targeting, biodistribution, barrier transport, and release initiation. Layer-by-layer (LbL) engineering provides a modular strategy for programming this interface through sequentially assembled coatings in which functional components are spatially separated yet mechanistically coordinated. By integrating polymers, biomolecules-including peptides and nucleic acids-and stimuli-responsive materials, LbL systems can decouple functions that are difficult to regulate independently within conventional single-layer or compositionally mixed surface architectures. This review examines recent advances in LbL-engineered LBNs (LbL-LBNs), focusing on how multilayer surface architecture reshapes physicochemical properties, cargo localization and release, biological identity, cellular interactions, and transport across physiological barriers. Particular attention is given to the multilayer interface as a dynamic biointerfacial bridge between a cargo-specific core architecture and the surrounding biological environment, including its capacity for stimuli-responsive switching in pathological microenvironments. The discussion further extends to biomimetic hybrid interfaces and establishes a framework for translating hierarchical surface architectures into reproducible, clinically tractable platforms for precision therapeutic delivery.
    Keywords:  bio-polymer; combination therapy; hierarchical structure; layer by layer system; lipid-based nanocarrier
    DOI:  https://doi.org/10.3390/pharmaceutics18091062
  6. Pharmaceutics. 2026 Aug 30. pii: 1094. [Epub ahead of print]18(9):
      Gene therapy and genome editing increasingly depend on the safe, effective, and cell-selective delivery of nucleic acids and protein-nucleic acid complexes. Although viral vectors remain important for applications requiring durable gene expression, non-viral vectors offer advantages in cargo capacity, modularity, transient expression, potential repeat dosing, and avoidance of vector-genome integration. Lipid nanoparticles (LNPs), polymeric nanoparticles, inorganic nanomaterials, extracellular vesicles (EVs), and biomimetic hybrid systems have consequently become central platforms for delivery of siRNA, mRNA, plasmid DNA, antisense oligonucleotides, and CRISPR-based genome editors. Among these, ionizable LNPs are currently the most clinically mature non-viral technology, supported by the clinical success of siRNA therapeutics and mRNA vaccines, as well as the emergence of in vivo CRISPR therapies. Nevertheless, efficient endosomal escape, cell-type-selective targeting, extrahepatic delivery, and repeat-dose tolerability remain substantial barriers. Polymeric vectors provide broad chemical tunability, allowing adjustment of charge density, degradability, stimulus responsiveness, intracellular trafficking, and cargo release. However, toxicity and batch-to-batch reproducibility remain key concerns. EVs provide a biologically derived alternative with favorable membrane interfaces and potential advantages for protein and ribonucleoprotein delivery, but their clinical translation is constrained by heterogeneity, loading efficiency, product characterization, and scalable manufacturing. This review summarizes recent advances in non-viral gene-delivery platforms, compares their strengths and limitations, and discusses future directions in cell-selective delivery, endosomal escape, transient delivery of genome-editing machinery, engineered EVs, hybrid vectors, and manufacturing-oriented development. The field is transitioning from organ-level delivery toward delivery of the correct payload to the correct cell type at a clinically relevant exposure and safety margin.
    Keywords:  CRISPR; extracellular vesicles; gene delivery; gene therapy; genome editing; lipid nanoparticles; mRNA delivery; non-viral vectors; polymeric nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics18091094
  7. ACS Appl Bio Mater. 2026 Sep 23.
      Extracellular vesicles such as exosomes are expected to be used as drug delivery vehicles, particularly in personalized medicine, due to their pharmacological advantages. However, the development of functionalization techniques for isolated extracellular vesicles-including improving their intracellular uptake efficacy from the perspective of a drug delivery system and targeting disease-associated cells to reduce side effects-has become an urgent priority. The aim of this study was to develop a technology for modifying the surface of exosome membranes with functional molecules using membrane-curvature-sensing peptides. By using a cassette-based approach to modify the surface of exosomes with functional peptides that induce macropinocytosis, this technology achieved highly efficient intracellular delivery of exosomes. Furthermore, we applied this technology to boron neutron capture therapy (BNCT). By encapsulating therapeutic boron agents within exosomes, effective induction of cancer cell death through thermal neutron irradiation in BNCT was achieved.
    Keywords:  boron neutron capture therapy; exosome functionalization; extracellular vesicles; macropinocytosis; membrane modification; membrane-curvature-sensing peptides
    DOI:  https://doi.org/10.1021/acsabm.6c00698
  8. J Nanobiotechnology. 2026 Aug 13. pii: 892. [Epub ahead of print]24(1):
      The therapeutic efficacy of ischemic stroke (IS) treatment is severely limited by insufficient accumulation of therapeutic agents within ischemic lesions and persistent secondary injury after ischemia-reperfusion. Herein, we report a cRGD-functionalized exosome-based nanoplatform that enhances ischemic lesion-associated accumulation and antioxidative neuroprotection for the treatment of IS. Neural stem cell-derived exosomes were functionalized with cyclic RGD peptides (cRGD) and subsequently loaded with Mn₃O₄ nanoparticles to construct a hybrid nanosystem (cRGD-Exo@Mn₃O₄). The engineered exosomes preserve intrinsic brain tropism, while cRGD modification promotes preferential accumulation in ischemic regions, potentially through interaction with αvβ3 integrin that is upregulated in ischemic lesions. The incorporated Mn₃O₄ nanoparticles confer robust reactive oxygen species (ROS) scavenging capability, thereby mitigating oxidative stress in ischemic microenvironments. In vitro and in vivo studies demonstrate that cRGD-Exo@Mn₃O₄ exhibits enhanced accumulation in ischemic regions compared with non-modified counterparts. The nanosystem effectively attenuates oxidative stress and neuroinflammation, leading to reduced infarct volume, alleviation of cerebral edema, and improved neurological function in MCAO/R mice. Mechanistically, transcriptomic analysis suggests that the therapeutic effects are associated with modulation of inflammation-and cell death-related pathways, including suppression of the RIPK1/RIPK3/MLKL signaling cascade. Collectively, this study presents a rationally designed exosome-based nanoplatform integrating ischemic lesion-associated accumulation with ROS-scavenging capability.
    Keywords:  Blood–brain barrier; Engineered exosomes; Ischemic lesion accumulation; Ischemic stroke; Mn₃O₄ nanozymes; Necroptosis; Oxidative stress
    DOI:  https://doi.org/10.1186/s12951-026-04922-0
  9. Nat Commun. 2026 Aug 25. pii: 10180. [Epub ahead of print]17(1):
      Vitreoretinal fibrosis, a hallmark of proliferative vitreoretinopathy (PVR) triggered by retinal detachment or ocular trauma, necessitates surgery. Through data mining of the vitreoretinal fibrosis microenvironment in PVR patients and mice, showing elevated transforming growth factor β1 (TGFβ1) and M2 macrophage enrichment, we designed and engineered extracellular vesicles that conferred anti-fibrotic efficacy against PVR. These M1 macrophage-derived vesicles (M1evs) were conjugated with anti-TGFβ1 antibodies (aT) via MMP-cleavable linkers (aT-cl-M1ev, termed ACE). Upon intravitreal injection in female PVR model mice, ACE selectively accumulates in lesions, where released antibodies neutralize TGFβ1 and M1evs inhibit M2 macrophage polarization, modulating the microenvironment to diminish vitreoretinal fibrosis. Further incorporating anti-platelet-derived growth factor receptor antibodies yields aTP-cl-M1ev (ACEPlus) to prevent retinal detachment progression in advanced-stage PVR, an efficacy validated in a patient-derived PVR membrane xenograft model. Therapeutic modulation of the vitreoretinal fibrosis microenvironment with the ACE platform provides an efficacious alternative to surgery for PVR.
    DOI:  https://doi.org/10.1038/s41467-026-76550-z
  10. Small. 2026 Sep 24. e75883
      Mitochondrial transfer has emerged as a promising therapeutic strategy for disease driven by neural and pain-related pathologies. However, inefficient intracellular delivery and severe lysosomal degradation significantly limit its translational potential. Given the critical role of mitochondrial dysfunction in Schwann cells (SCs) and macrophages during neuropathic pain progression in temporomandibular joint arthritis and knee osteoarthritis, this study presents an optimised nanomedicine treatment approach using mitochondria-derived extracellular vesicles (MitoEVs). Here, we isolated functional MitoEVs from SCs for surface modification with a novel micellar material, R8-HDA (yielding R-MitoEVs), to enhance efficient endosomal escape. Our results demonstrate that R-MitoEVs exhibit augmented cellular uptake and enhance evasion of lysosomal degradation, thereby preserving the structural integrity and bioactivity of the transferred mitochondria. Consequently, R-MitoEVs suppressed lipopolysaccharide-induced pro-inflammatory macrophage polarisation and downregulated TNF-α/NF-κB signalling. Concurrently, the R-MitoEV-derived mitochondria restored metabolic homeostasis in SCs by quenching reactive oxygen species and augmenting antioxidant capacity. In vivo evaluations demonstrated the therapeutic efficacy of R-MitoEVs, characterised by enhanced chondrocyte resilience and the significant downregulation of pain-related neuronal markers (TRPV1 and CGRP) and pro-inflammatory mediators. Overall, this surface-engineered R-MitoEVs platform mitigates the biological barriers of mitochondrial delivery, offering a promising therapeutic strategy for mitigating osteoarthritis and its associated neuropathic pain.
    Keywords:  TRPV1; chondrocyte; downregulation and upregulation; extracellular vesicle; macrophage; microvesicles; mitochondrion; neuropathic pain; osteoarthritis; reactive oxygen species
    DOI:  https://doi.org/10.1002/smll.75883
  11. Methods Mol Biol. 2027 ;3075 219-235
      Extracellular vesicles (EVs), particles released from cells, have the potential to become an important in vivo delivery vehicle for CRISPR machinery. Unlike viral vectors such as Adeno-associated virus (AAV), EVs reduce risks associated with immunogenicity, long-term expression, and potential off-target effects. EVs can efficiently deliver CRISPR/Cas9 ribonucleoprotein (RNP) complexes, which provide transient, ready-to-function editing machinery with reduced off-target risk compared with plasmid DNA or mRNA delivery. RNP loading into EVs can occur without specific targeting signals, although strategies such as membrane anchoring, inducible dimerization systems, or fusion with EV-associated proteins can enhance cargo enrichment. EVs are typically produced by transfecting producer cells with plasmids encoding Cas9 and sgRNA, followed by vesicle release into culture media. Purification requires removal of cellular debris and enrichment of vesicles using methods such as ultracentrifugation, ultrafiltration, chromatography, or precipitation. As no single gold-standard purification approach exists, method selection should balance yield and purity, and characterization using vesicle markers and size distribution profiling is recommended.
    Keywords:  CRISPR/Cas9; Exosomes; Extracellular vesicles; In vivo delivery; Microvesicles; Ultracentrifugation
    DOI:  https://doi.org/10.1007/978-1-0716-5547-4_11
  12. Int J Mol Sci. 2026 Sep 19. pii: 8326. [Epub ahead of print]27(18):
      Age-related degeneration remains a premier biomedical challenge, frequently underpinned by cellular senescence and stem cell dysfunction. Accumulating evidence suggests that umbilical cord mesenchymal stromal cell (UC-MSC)-derived extracellular vesicles (UC-EVs) and the longevity protein Klotho hold great promise as anti-aging biotherapeutics. Here, we strategically engineered UC-MSCs to overexpress Klotho and generated functional Klotho-enriched UC-EVs (KL-EVs). Our data demonstrated that genetic modification endowed UC-MSCs with prominent osteogenic differentiation potency and angiogenesis efficacy. More importantly, KL-EVs profoundly rescued multifaceted senescent phenotypes in both adult bone marrow mesenchymal stem cells (BMSCs) and human renal tubular epithelial cells (HK-2) in vitro. In particular, KL-EVs rescued the age-related differentiation bias of adult BMSCs by robustly prompting their osteogenic differentiation capacity. Taken together, we developed a novel type of UC-MSCs and isolated their EVs enriched with Klotho protein. This strategy integrated and enhanced the anti-aging effects of both entities in vitro, offering a new perspective for counteracting cellular senescence and alleviating age-associated degenerative alterations.
    Keywords:  cellular senescence; extracellular vesicles; klotho; mesenchymal stromal cells; osteogenic differentiation
    DOI:  https://doi.org/10.3390/ijms27188326