bims-engexo Biomed News
on Engineered exosomes
Issue of 2025–09–07
fourteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur



  1. J Med Chem. 2025 Sep 05.
      Familial hypertriglyceridemia (FHTG), a severe subtype of primary hypertriglyceridemia caused by mutations in GPIHBP1 and other related genes, is linked to life-threatening cardiovascular complications. Current therapies inadequately address the underlying genetic pathology. Here, we developed a novel exosome-based mRNA delivery platform to restore functional glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) expression, providing a targeted therapeutic strategy for FHTG. Using GPIHBP1-/- mice as disease models, we engineered exosomes (ExoGPIHBP1) encapsulating GPIHBP1 mRNA via an optimized vector. These exosomes exhibited high biostability and preferential liver accumulation after systemic administration, enabling efficient protein translation. Consequently, treatment significantly reduced serum triglyceride (TG) levels, attenuated lipid accumulation, and ameliorated liver steatosis. Our study explores exosome-mediated GPIHBP1 mRNA therapy as a precise, safe, and effective strategy for FHTG, highlighting a considerable translational potential for genetic dyslipidemias. The platform advances RNA-based therapeutics by bridging the gap between gene therapy and clinical applications.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c01828
  2. Adv Mater. 2025 Aug 29. e05714
      Precise delivery of pharmaceuticals administered to bone marrow for various bone diseases is challenging, given the bone marrow-blood barrier (MBB). Bone marrow stromal cells (BMSCs) derived from bone marrow can naturally infiltrate the MBB and home to bone tissue. Here, biomimetic nanovesicles (namely mNVs) engineered with the extracted cell membrane from BMSCs are reported for homing delivery of different core nanomedicines to bone marrow. The cargo-loaded mNVs exhibited excellent bone targeting in crossing natural barriers is demonstrated to augment drug concentrations in bone marrow, and the bio-function of mNVs is verified in typical models of chronic metabolic bone disease and metastatic carcinoma. In the induced osteoporosis model, engineered mNVs deliver the nanocore of teriparatide-loaded poly(lactic-co-glycolic acid), forming a sustained-release system of teriparatide, which can significantly slow bone loss, maintain bone mass, and alleviate osteoporosis indicators. In osseous and systematic metastatic breast carcinoma models, the mNVs are employed to deliver DNA tetrahedron embedded doxorubicin and efficiently inhibit tumor progression and osteolytic lesions. This work suggests that high-efficiency bone marrow delivery of medications can be camouflaged by the cell membrane derived from BMSCs, initiating a new platform for bone targeting drug delivery for developing more effective therapeutics for bone diseases.
    Keywords:  biomimetic nanovesicle; bone marrow stromal cells; cell membrane coating; metastatic breast cancer; osteoporosis; teriparatide; tetrahedral framework nucleic acid
    DOI:  https://doi.org/10.1002/adma.202505714
  3. Front Immunol. 2025 ;16 1628573
      Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, whose progression is intimately linked to the complex dynamics of the tumor microenvironment (TME). Exosomes, once considered mere cellular waste, have emerged as pivotal mediators of intercellular communication within the TME, actively participating in the multistep development of HCC. These nanoscale vesicles play crucial roles in the initiation of precancerous lesions and, by transporting drug resistance-related molecules such as proteins and non-coding RNAs, facilitate the acquisition of resistance to chemotherapy and targeted therapies by tumor cells. Moreover, exosomes contribute to the establishment of pre-metastatic niches by remodeling distant organ microenvironments-inducing hypoxia, metabolic reprogramming, and angiogenesis-which collectively create favorable conditions for tumor cell colonization. They also modulate immune responses by inducing T-cell exhaustion, promoting macrophage polarization, and disrupting normal stromal cell functions, thereby constructing an immunosuppressive microenvironment that enables tumor immune evasion. Given their inherent biocompatibility and targeting capabilities, engineered exosomes have shown promise in cancer therapy, serving as carriers for therapeutic molecules and enabling precise drug delivery through surface modifications. Despite significant advancements, challenges remain in elucidating the in vivo regulatory mechanisms of exosomes, standardizing their isolation and purification processes, and evaluating their clinical efficacy. This review examines the multifaceted roles of exosomes in HCC, aiming to bridge mechanistic insights with precision diagnostics and pave new avenues for liver cancer treatment.
    Keywords:  drug tolerance; exosomes; hepatocellular carcinoma (HCC); metastasis; targeted therapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1628573
  4. Int J Nanomedicine. 2025 ;20 10407-10431
      The repair and functional regeneration of spinal cord injury (SCI) remains a major challenge and focal point in regenerative medicine. Following SCI significant inflammation and neuronal damage occur. Conventional drug therapies often fail to precisely target the injured areas and cannot cross the blood-spinal cord barrier, severely limiting therapeutic efficacy. Therefore, precision therapeutics are crucial to improve the prognosis of SCI patients. In recent years, exosomes have gained widespread attention as natural delivery vehicles due to their low immunogenicity, high biocompatibility, and efficient delivery capabilities. Exosomes can effectively cross cell membranes and target specific cells, playing an important role in intercellular signaling. This makes them highly promising for precision therapies in SCI. By engineering exosomes for targeted delivery, new strategies can be developed for drug delivery, gene therapy, and personalized treatment after SCI. We aimed to review the biological functions of exosomes derived from different cell sources and discuss the role in tissue repair following SCI. Additionally, we explore the prospects and potential of exosomes in clinical SCI applications, to provide valuable research insights to improve functional recovery and long-term health management for SCI patients in the future.
    Keywords:  exosomes; inflammation; nanodelivery; nerve injury; non-coding RNA; spinal cord injury
    DOI:  https://doi.org/10.2147/IJN.S539673
  5. Int J Nanomedicine. 2025 ;20 10195-10212
       Background: Premature ovarian insufficiency (POI) is a persistent condition in young women characterized by early follicular development disorders and reduced fertility. Research has found that exosomes derived from human umbilical mesenchymal stem cells (hUCMSC-Exo) have significant tissue repair effects. This study aims to investigate the therapeutic effect and potential molecular mechanism of hUCMSC-Exo on POI.
    Methods: In vivo experiments were conducted by intraperitoneally injecting the chemotherapy drug cyclophosphamide (CTX) to establish a 14-day POI rat model. Serum hormone levels were measured using an enzyme-linked immunosorbent assay, and changes in ovarian tissue structure were analyzed using hematoxylin-eosin (HE) staining. Perls staining and transmission electron microscopy were used to assess changes in ovarian ferroptosis. In vitro experiments involved exposing theca interna cells (TICs) treated with CTX to normal and miR-26a-5p inhibitor-treated hUCMSC-Exo. The expression changes of PTEN, Nrf2, and GPX4, which are associated with ferroptosis, were analyzed using immunofluorescence, Western blot, and quantitative reverse-transcription polymerase chain reaction.
    Results: hUCMSC-Exo intervention can significantly repair the ovarian tissue structure and functional abnormalities in the model rats, especially ferroptosis. Further bioinformatics analysis revealed that the inhibition of the PTEN/GPX4 pathway-mediated ferroptosis in TICs might be the main mechanism through which exosomes exert their regulatory/therapeutic effects. In vitro experiments, where exosome miR-26a-5p was inhibited, further confirmed that the delivery of miR-26a-5p is crucial for the regulatory effect of exosomes.
    Conclusion: In conclusion, our results suggest that hUCMSC-Exos alleviates POI-related dysfunction of ovarian structure and function. The mechanism could be related to the transfers of miR-26a-5p and suppression of PTEN/GPX4 axis signaling-mediated autophagy of TICs. It provides a new perspective for developing treatment methods for patients with metabolic abnormalities related to POI.
    Keywords:  GPX4; POI; TICs; ferroptosis; hUCMSC-Exo; miR-26a-5p
    DOI:  https://doi.org/10.2147/IJN.S532207
  6. Biology (Basel). 2025 Aug 13. pii: 1040. [Epub ahead of print]14(8):
      Skin aging is commonly characterized by increased wrinkles, loss of elasticity, and hyperpigmentation, significantly affecting personal appearance and quality of life. Although botulinum toxin type A (BTX-A) has been widely applied in cosmetic anti-wrinkle treatments, its intrinsic cytotoxicity limits broader clinical applications. In this study, we developed a novel exosome-based BTX-A composite delivery system designed to synergize the anti-aging properties of exosomes with the wrinkle-reducing effects of BTX-A while reducing toxicity. Human adipose-derived mesenchymal stem cells were genetically modified via lentiviral transduction to overexpress Synaptic Vesicle Glycoprotein 2C (SV2C), the receptor of BTX-A, thereby producing SV2C-enriched functionalized exosomes (EXOSV2C). These exosomes (2.0 × 107 particles/mL) were incubated with BTX-A (3 U/mL) to generate the EXOSV2C-BTX-A complex. In vitro, EXOSV2C-BTX-A significantly promoted the proliferation and migration of human dermal fibroblasts and effectively alleviated D-galactose (D-gal)-induced cellular senescence and collagen type I loss. These effects were superior to those observed with either BTX-A or exosomes alone. In vivo, intradermal injection of EXOSV2C-BTX-A for 28 days markedly suppressed D-gal-induced skin aging in 8-week-old male KM mice, as evidenced by reduced malondialdehyde levels in dermal tissue, enhanced collagen type I expression, and preserved skin structure. Notably, the composite exhibited significantly lower toxicity compared to free BTX-A. Collectively, these findings highlight EXOSV2C-BTX-A as a promising exosome-mediated BTX-A delivery platform with enhanced anti-aging efficacy and improved biocompatibility, offering a potential therapeutic strategy for skin rejuvenation.
    Keywords:  adipose stem cells; botulinum toxin type A; cellular senescence; exosomes; synaptic vesicle glycoprotein 2C
    DOI:  https://doi.org/10.3390/biology14081040
  7. Sci Rep. 2025 Sep 01. 15(1): 32226
      Spinal cord injury (SCI) is a condition of the central nervous system, results in impairments in both sensory and motor functions. Presently, there exists a deficiency in efficacious therapies. Nonetheless, employing exosomes, a derivative of human umbilical cord mesenchymal stem cells (hucMSCs), is proven to be a successful approach in treating SCI, yet the exact way they function is still not well understood. Our research involved conducting a laminectomy on mice's thoracic T8-T10 and subsequently striking the revealed spinal cord using an altered Allen's weight descending apparatus (8 g, height 50 mm, 8 g × 50 mm) to create a model for SCI animals. To create a model of BV2 inflammation, BV2 cells underwent a 24-hour treatment with 1 µg/mL LPS. The expression of related genes and proteins was identified using RT‒qPCR and western blot. ELISA, immunofluorescence staining, and HE staining were employed to assess the polarization of BV2 cells and spinal cord tissue damage in mice. The research indicated that exosomes originating from hucMSCs are capable of markedly hindering the M1 polarization in BV2 cells, diminishing inflammation, and lessening the progression of SCI in vivo. From a mechanistic standpoint, exosomes originating from hucMSCs suppressed iNOS and CD16 levels, enhanced Arg1 and CD206 expression, lessened BV2 cells' M1 polarization, and concurrently suppressed LPS-triggered inflammatory cytokines IL-6, TNF-α, and IL-1β, ultimately easing LPS-triggered inflammation and mitigating SCI progression. The impact of exosomes derived from hucMSCs primarily resulted from the enhancement of miR-340-5p expression, which in turn suppressed the JAK/STAT3 signaling pathway. The findings of our research indicate that exosomes derived from hucMSCs could represent an innovative approach in treating SCI.
    Keywords:  Exosomes; Human umbilical cord mesenchymal stem cells; JAK/STAT3 signaling pathway; Microglial polarization; Spinal cord injury; miR-340-5p
    DOI:  https://doi.org/10.1038/s41598-025-16621-1
  8. Oncol Lett. 2025 Oct;30(4): 487
      Cancer-associated mesenchymal stem cells (CA-MSCs) modulate the tumor microenvironment and promote tumor progression. The present study aimed to investigate the effects of CA-MSCs, CA-MSC-derived exosomes and CA-MSC exosome-derived microRNA (miR)-182 on non-small cell lung cancer (NSCLC) cell viability and invasiveness. CA-MSCs were established by treating MSCs with supernatant from NSCLC cells. Then, two NSCLC cell lines (A549 and H1299) were treated with CA-MSCs, CA-MSCs + GW4869 (inhibits exosomes) and CA-MSC exosomes. Additionally, miR-182 inhibitor was added to CA-MSCs and the related exosomes were used to treat NSCLC cells. Furthermore, miR-182 mimic and F-box and WD repeat domain containing 7 (FBXW7) overexpression vector were used to treat NSCLC cells. The results indicated that CA-MSCs promoted NSCLC cell viability and invasiveness and inhibited cell apoptosis, an effect that was attenuated following GW4869 treatment. The CA-MSC exosomes also enhanced NSCLC cell viability and invasiveness while inhibiting cell apoptosis. In addition, CA-MSC exosomes elevated miR-182 expression in NSCLC cells. Subsequently, CA-MSC exosomes with miR-182 expression knockdown exhibited a weakened effect on NSCLC cell viability, apoptosis and invasiveness compared with control CA-MSC exosomes. Direct miR-182 mimic transfection enhanced NSCLC cell viability and invasiveness and inhibited cell apoptosis, an effect that was attenuated by transfection with the FBXW7 overexpression vector. Furthermore, miR-182 negatively regulated and sponged FBXW7 expression in NSCLC cells. Finally, treatment of the cells with miR-182 mimic increased the phosphorylated (p-)AKT and p-ERK1/2 expression levels, while treatment with the FBXW7 overexpression vector decreased these levels in NSCLC cells. In summary, CA-MSCs facilitated NSCLC viability and invasiveness via transmitting exosomal miR-182 in a FBXW7-related AKT and ERK-dependent pathway.
    Keywords:  F-box and WD repeat domain containing 7; cancer-associated mesenchymal stem cells; exosomes; lung cancer; microRNA-182
    DOI:  https://doi.org/10.3892/ol.2025.15233
  9. J Drug Target. 2025 Sep 03. 1-24
      The aim of the study was to explore the potential of human plasma-derived exosomal gel as a carrier for transdermal drug delivery. Exosomes were isolated from human plasma through a combination of ultracentrifugation and dialysis techniques. Methotrexate (MTX), a weak acid drug with log P 1.53 (low permeability), was utilized as a model drug. MTX was loaded into exosomes using the freeze-thaw method. MTX-loaded exosomes were incorporated into a gel, employing carbopol 940 as a gelling agent. MTX loaded exosomes exhibited a mean size of 162.15 ± 4.21 nm, a polydispersity index (PDI) 0.372 ± 0.024, and a zeta potential of -30.6 ± 0.71 mV. Exosomal gel displayed good physicochemical properties along with desirable rheological behavior that eased skin application. MTX-loaded exosomal gel exhibited sustained release of 59.14 ± 0.812% of the drug within 72 hours at pH 7.4 as compared to nonexosomal gel p < 0.0001. MTX-loaded exosomal gel demonstrated a three-fold increase in skin permeability as compared to MTX loaded gel. Moreover, results of in-vivo studies on the carrageenan-induced inflammation model indicated exosomal gel and MTX loaded exosomal gel reduced inflammation as compared to MTX gel. These findings suggested the potential of exosomes as an emerging platform for transdermal drug delivery, offering enhanced skin penetration.
    Keywords:  Exosomal gel; Methotrexate; Skin permeability; Transdermal drug delivery; human plasma-derived exosomes
    DOI:  https://doi.org/10.1080/1061186X.2025.2556196
  10. Physiol Res. 2025 Aug 31. 74(4): 589-599
      To establish a co-culture cell model and implement high-throughput gene sequencing of exosomes, we preliminarily demonstrated that endothelial cell-derived exosomes play a role in modulating the phenotypic transformation of vascular smooth muscle cells (VSMCs) by means of differentially expressed long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Primary rat aortic endothelial cells (ECs) and VSMCs were cultured for morphological observation, immunofluorescence (IF), and western blotting (WB). A co-culture model was established using a transwell system. A comparative analysis of ?-smooth muscle actin (?-SM actin), a marker of the contractile phenotype, and vimentin, indicative of the synthetic phenotype, was conducted to assess the expression levels in both co-culture and control setups. Isolated exosomes were obtained using an exosome-specific isolation kit, followed by detailed characterization using transmission electron microscopy (TEM) for morphological assessment, nanoparticle tracking analysis (NTA) for size distribution, and WB for protein profiling. Primary aortic ECs were isolated, cultured, and characterized. In the Transwell co-culture model, VSMCs transitioned to a contractile phenotype, exhibiting increased alpha-smooth muscle actin (?-SMA, contractile marker) and decreased Vimentin (synthetic marker). Exosomes were extracted, purified, and characterized by their morphology, diameter, concentration, and marker proteins (CD9, CD63, and CD81). RNA-seq and bioinformatic analyses were conducted on muscle cells before and after treatment. The Transwell-based ECs-VSMCs co-culture model significantly upregulates contractile phenotype protein expression in VSMCs, promoting their transition to a contractile state. Differentially expressed exosomal genes, including lncRNAs and circRNAs, modulate proliferation, differentiation, and phenotypic transformation of VSMCs.
  11. Cell Rep Med. 2025 Aug 22. pii: S2666-3791(25)00392-1. [Epub ahead of print] 102319
      Oxidative damage and neuroinflammation are the key features of central nervous system (CNS) injury. Inspired by the neuroprotective properties of neural stem cell-derived exosomes (NExo) and the reactive oxygen species (ROS) scavenging ability of selenium, we develop an advanced NExo bearing ultrasmall nano-selenium (∼3.5 nm) via lipid-mediated nucleation (SeNExo). In addition to maintaining the biological components of NExo, the resulting SeNExo exhibits a Se-O bond that dramatically enhances its ROS-scavenging performance. SeNExo penetrates the blood-brain barrier (BBB) via the apolipoprotein E and prolow-density lipoprotein receptor-related protein 1 (APOE_LRP-1) interaction. Through proteomics, microRNA (miRNA) omics, and single-nucleus RNA sequencing, we find that SeNExo can alleviate neuronal apoptosis, restore glia homeostasis, and remodel glia-neuron networks. Therefore, SeNExo confers potent therapeutic benefits, significantly reducing cerebral lesions in a murine traumatic brain injury model. Even extending to a murine spinal cord injury model, SeNExo promotes locomotory recovery, further supporting SeNExo as a neotype and a promising therapeutic agent for treating traumatic CNS injury.
    Keywords:  exosomes; neuroinflammation; oxidative stress; selenium; traumatic brain injury; traumatic spinal cord injury
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102319
  12. Int Immunopharmacol. 2025 Aug 30. pii: S1567-5769(25)01433-X. [Epub ahead of print]165 115442
      In recent years, the roles of Exosomes in tumors and infectious diseases have been found to have potential application value in disease diagnosis and treatment. However, whether Exosomes are involved in host-acquired immune responses against Brucella has not been reported. This study explored the significance of Exosomes in the context of Brucella infection and their influence on host immune responses. Additionally, we assessed the immunoprotective efficacy of these Exosomes in a murine model. The findings demonstrate that Exosomes played an important role in immune regulation during Brucella infection, enhancing the host's anti-Brucella immune response and inhibiting intracellular bacterial survival. A novel mechanism by which antigens are transmitted between immune cells through Exosomes to initiate an adaptive immune response against Brucella was also identified. These insights contribute to a deeper understanding of Brucella pathogenesis and host immune regulation, offering a promising avenue for the development of innovative Brucella vaccines or immune adjuvants for brucellosis.
    Keywords:  Brucella; Exosomes; Immunity
    DOI:  https://doi.org/10.1016/j.intimp.2025.115442
  13. Cell Biochem Funct. 2025 Sep;43(9): e70114
      Polycystic ovary syndrome (PCOS), the most common endocrine syndrome in females, remains a human health problem worldwide. Nano-based drug delivery system has emerged as a novel therapy against PCOS. Recent developments in nanotechnology have led to the innovation of synthetic and natural-based nanoparticles (NPs) that deliver therapeutic agents to PCOS. The synthetic NPs, including Ag-NPs, selenium-NPs, Cu-NPs/Fe3O4-NPs, superparamagnetic iron oxide NPs, and chitosan-NPs, as well as natural NPs such as nanocurcumin and exosomes, are used to combat PCOS. Exosomes are cell-derived NPs that regulate cell-to-cell communication. Exosomes from stem cells showed promising results regarding the treatment of PCOS. It seems that the application of NPs in PCOS is not widely understood. Although the Nano-based drug delivery system showed beneficial effects against PCOS, this approach faces some challenges. Further innovation and investigations in clinical and preclinical platforms are needed for clinical translation. This paper is an overview of the application of synthetic and natural NPs in treating PCOS. In addition, the present paper aims to describe exosome-based therapy in PCOS while shedding light on the perspective of nano-based drug delivery systems.
    Keywords:  PCOS; drug delivery system; exosomes; nanoparticles
    DOI:  https://doi.org/10.1002/cbf.70114
  14. Brain Res Bull. 2025 Aug 28. pii: S0361-9230(25)00339-9. [Epub ahead of print] 111527
      Major depressive disorder (MDD) is a multifaceted mental disorder marked by a spectrum of significant and persistent low mood symptoms. Its etiology involves genetic and environmental factors. In addition, the inflammatory process plays a crucial role in the pathophysiology of depression. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) have demonstrated significant effects in reducing proinflammatory cytokines. However, there is limited research on whether exosomes can prevent the occurrence of LPS-induced depression. This study aimed to investigate the role of BMSC-derived exosomes in LPS-induced depression and explore the underlying mechanisms. We administered exosomes to LPS-induced depression mice via the caudal vein and evaluated their effects on depressive-like behaviors. Our findings indicate that four injections of exosomes (200µl at a concentration of 1.4×10¹¹ particles/ml, administered every three days) significantly prevented depressive-like behaviors in LPS-induced depression mice. Further analyses revealed that exosome treatment reduced levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and increased anti-inflammatory cytokine IL-10. Additionally, exosome treatment markedly reduced oxidative stress in both the central and peripheral nervous systems of LPS-treated mice. Moreover, our data suggest that exosome treatment increased astrocyte proliferation and neurogenesis in the hippocampus of LPS mice. In summary, our results demonstrate the antidepressant effects of BMSC-derived exosomes in LPS-induced depression mice, suggesting a potential new therapeutic target for major depressive disorder (MDD).
    Keywords:  Exosome; Inflammation; MSCs; depression
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111527