bims-engexo 2025-12-21 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–12–21
twelve papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineering exosomes for Alzheimer's disease: Multi-target therapeutic strategies from pathogenesis to clinical translation.
Engineered hUCMSC-derived extracellular vesicles deliver circ-0000258 to restore p53-mediated tumor suppression in papillary thyroid carcinoma.
Stem Cells Derived Suicide Gene Exosomes; a Promising Platform for Innovative Cancer Therapy.
Induction of antigen-specific regulatory T cells by engineered extracellular vesicles.
Engineered extracellular vesicles-mediated curcumin delivery in brain microenvironment modulating lysosomes, mitochondria, and microglia reprogram for parkinson's disease therapy.
Bioengineered Anti-PD-L1 Functionalized Nanoplatform for Targeted Delivery and Tumor Immune Reprogramming Against Colorectal Cancer.
GPX4-overexpressing mesenchymal stem cell-derived exosomes ameliorate secondary brain injury after intracerebral hemorrhage by inhibiting neuronal ferroptosis.
Gentamicin-loaded exosomes from IMMUNEPOTENT CRP enhance healing of infected diabetic wound in mice.
Hybrid Extracellular Vesicles for Efficient Loading and Functional Delivery of mRNA.
Exosome-mediated scutellarin delivery enhances BBB penetration and microglia targeting in antiviral neuroprotection.
Targeted Intracellular Delivery via Precision Programming of ARRDC1-Mediated Microvesicles.
Engineered Plant-Derived Extracellular Vesicles as Targeted Drug Carriers in Cancer Therapy.

Clin Transl Med. 2025 Dec;15(12): e70548

Engineering exosomes for Alzheimer's disease: Multi-target therapeutic strategies from pathogenesis to clinical translation.

Yuehan Zhang, Zhenyang Li, Haien Guan, Zhenhua Qiu, Chunlin Zou.

  The complex pathogenesis of Alzheimer's disease (AD), combined with the presence of the blood‒brain barrier (BBB), severely limits the effectiveness of conventional therapeutic approaches. Engineered exosomes-nanoscale extracellular vesicles of natural origin-have emerged as a promising platform for innovative AD therapy due to their excellent biocompatibility, low immunogenicity and intrinsic ability to cross the BBB. This review provides a systematic overview of the synthetic and structural biological characteristics of exosomes, with a focus on their functionalisation through physical, chemical and genetic modifications. These approaches enable the targeted loading of therapeutic cargo and the conjugation of brain-targeting peptides, thereby facilitating precise delivery to specific brain regions and offering a multi-target therapeutic strategy for AD. We further examine the potential of engineered exosomes in modulating core AD pathological pathways, including amyloid-beta deposition, tau hyperphosphorylation, neuroinflammation and synaptic dysfunction, and highlight their utility as an integrated delivery system for the co-delivery of multiple therapeutic agents to achieve synergistic therapeutic effects. Finally, key challenges in clinical translation are addressed, such as scalable production, standardised drug loading protocols and comprehensive assessment of safety and immunogenicity. Unlike previous reviews that primarily focus on general engineering techniques, this article emphasises a rational design strategy tailored for multi-target synergistic therapy and presents a comprehensive roadmap from basic research to clinical application, thereby providing both theoretical insights and practical guidance for the development of next-generation AD treatments. KEY POINTS: A multidimensional approach combining physical, chemical, and genetic modifications equips exosomes with brain-targeted peptides, enhancing their capability for precise brain delivery in Alzheimer's disease (AD) Engineered exosomes are designed to cross the blood-brain barrier and provide stimuli-responsive release of therapeutic agents, enabling simultaneous clearance of amyloid-beta plaques and neurofibrillary tangles, and inhibition of neuroinflammation. The transition from preclinical success to early-phase human trials is underway, with intranasal administration emerging as a promising, non-invasive method for brain drug delivery. A well-defined plan for clinical translation includes scalable Good Manufacturing Practice (GMP) production, rigorous safety assessments, and biomarker-guided clinical trial design to facilitate clinical application.

Keywords:  Alzheimer's disease; blood‒brain barrier; clinical translation; engineered exosomes; multi‐target therapy; safety assessment; targeted delivery

DOI:  https://doi.org/10.1002/ctm2.70548
BMC Cancer. 2025 Dec 15. 25(1): 1868

Engineered hUCMSC-derived extracellular vesicles deliver circ-0000258 to restore p53-mediated tumor suppression in papillary thyroid carcinoma.

Chan Zhang, Lei Li, Yanxiu Liu, Bo Yu, Jing Liu, Shujing Li.

   INTRODUCTION: Papillary thyroid carcinoma (PTC) is a significant type of endocrine cancer, characterized by diverse genetic alterations and a complex molecular environment. Extracellular vesicles (EVs), especially those derived from mesenchymal stem cells (MSCs), have emerged as promising targeted drug carriers for cancer cells. Additionally, reprogramming MSC-derived EVs represents a novel strategy for cancer gene therapy, offering potential solutions to clinical challenges and new treatment directions. Increasing evidence suggests that MSC-derived EVs play a crucial role in tumor progression by delivering circular RNAs (circRNAs), which function as microRNA (miRNA) sponges. However, the underlying molecular mechanisms and their clinical applications remain to be fully explored and validated.
METHODS AND RESULTS: Through in-depth mining using high-throughput bioinformatics analyses, we conducted a comprehensive differential gene analysis between PTC tissues and normal thyroid tissues, successfully identifying circ-0000258 as a key regulatory molecule. Following multi-dimensional validation in PTC cell lines and clinical specimens, the consistent low expression of circ-0000258 was confirmed, strongly suggesting its latent potential as a tumor suppressor. Functional mechanistic investigations have revealed that overexpression of circ-0000258 potently curbs the malignant biological behaviors of PTC cells, notably inhibiting cell proliferation and invasion. More significantly, circ-0000258 acts as a molecular sponge, specifically sequestering miR-146b. This action relieves the post-transcriptional repression of p53 by miR-146b, thereby activating the p53-mediated apoptotic signaling cascade. By intervening at the genetic regulatory level, circ-0000258 effectively reprograms the fate of thyroid tumor cells. Furthermore, in the context of translational medicine research, we innovatively constructed an engineered delivery platform based on extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUCMSC-EVs). By exogenously loading circ-0000258 into these vesicles, we successfully endowed these natural nanocarriers with targeted anti-cancer properties. Both in vitro and in vivo functional assays demonstrated that the engineered hUCMSC-EVs loaded with circ-0000258 could effectively act on PTC cells, significantly reducing the volume of xenograft tumors and inducing tumor cell apoptosis. Notably, when combined with cisplatin, these engineered extracellular vesicles exhibited a synergistic anti-cancer effect, suggesting their potential to overcome chemoresistance in thyroid tumors.
CONCLUSION: This study has established the circ-0000258/miR-146b/p53 regulatory axis as a crucial mechanism underlying tumor suppression in PTC. It has also demonstrated the translational potential of hUCMSC-EVs as a safe and efficient delivery vehicle. By integrating the functional role of circ-0000258 with the targeted delivery advantages of engineered EVs, this research not only provides a novel strategy for the targeted treatment of thyroid cancer but also offers a theoretical basis and technical paradigm for the development of novel anti-tumor biological agents. It is anticipated to advance the field of precision oncology to a new level.

Keywords:  Circ-0000258; HUCMSC-Extracellular vesicles; Molecular sponge; P53 pathway; Papillary thyroid carcinoma

DOI:  https://doi.org/10.1186/s12885-025-15230-5
Neoplasma. 2025 Dec 19. pii: 251119N487. [Epub ahead of print]

Stem Cells Derived Suicide Gene Exosomes; a Promising Platform for Innovative Cancer Therapy.

Dajana Vanova, Michal Andrezal, Ursula Altanerova, Miroslava Matuskova, Cestmir Altaner.

Innovative cancer treatments are needed for metastatic tumors that currently do not have adequate therapies. This review highlights recent progress in suicide gene small extracellular vesicles, particularly exosomes as a new form of intracellular anti-cancer drug. Suicide gene exosomes are produced by tumor-targeting human mesenchymal stem cells that have been genetically modified to express the yeast cytosine deaminase::uracil phosphoribosyl transferase fused gene (yCD::UPRT) along with the prodrug 5-fluorocytosine (5-FC). The yCD::UPRT-MSC-secretome containing tumor targeted exosomes, convert 5-FC into the cytotoxic compound 5-fluorouracil (5-FU) and its metabolites within the tumor environment. The second popular system we are investigating involves the suicide gene exosomes derived from thymidine kinase of Herpes Simplex Virus in conjunction with a prodrug ganciclovir. Extracellular vesicles secreted by tumor associated cells contribute to tumor growth and metastasis. When these cells are transduced with yCD::UPRT suicide gene, they can act as a source of therapeutic exosomes capable of intracellularly converting nontoxic prodrug 5-FC to a cytotoxic 5-FU. Combined action of suicide gene exosomes from MSCs and cancer associated fibroblasts (CAFs) is a promising platform for aggressive tumors treatment. Furthermore, suicide gene exosomes can be enhanced with additional anti-cancer drugs and customized for targeted delivery. In this review, we trace the history of these findings, present therapeutic outcomes from in vitro and in vivo studies, and explore the future potential of therapeutically beneficial exosomes for cancer treatment.

DOI: https://doi.org/10.4149/neo_2025_251119N487
Drug Deliv. 2025 Dec;32(1): 2586305

Induction of antigen-specific regulatory T cells by engineered extracellular vesicles.

Shota Imai, Kanto Nagamori, Uryo Onishi, Xiabing Lyu, Iriya Fujitsuka, Makie Ueda, Tomoyoshi Yamano, Rikinari Hanayama.

  Extracellular vesicles (EVs) are emerging as versatile nanocarriers for targeted drug delivery and immune modulation. However, strategies that can induce antigen-specific immune tolerance remain limited, highlighting an unmet need for more precise and effective approaches. To address this challenge, we aimed to develop a modular EV-based system capable of inducing antigen-specific regulatory T cells (Tregs). In this study, we developed engineered antigen-presenting EVs (AP-EVs) that co-display peptide-major histocompatibility complex class II complexes (pMHCII), interleukin-2 (IL-2), and transforming growth factor-β (TGF-β) on their surface. These immunomodulatory molecules were anchored to the EV membrane via CD81 or milk fat globule-EGF factor 8 (MFG-E8) scaffolds to ensure stable and multivalent presentation. AP-EVs induced the differentiation of antigen-specific Tregs from naïve CD4⁺ T cells in vitro, and promoted their proliferation and expression of canonical regulatory markers, including CD25, CTLA-4, PD-L1, and LAG-3. In vivo, the combination of AP-EVs and mTOR inhibition with rapamycin significantly enhanced the generation of Foxp3⁺ Tregs in antigen-specific adoptive transfer models. The Tregs induced by AP-EVs in vitro exhibited suppressive function, highlighting the therapeutic potential of this system. Our findings establish a modular, cell-free EV platform for antigen-specific immune tolerance, with potential applications in the treatment of autoimmune and allergic diseases through targeted immune regulation.

Keywords:  Extracellular vesicles; TGF-β; antigen-specific immunotherapy; exosome; immune tolerance; regulatory T cells

DOI:  https://doi.org/10.1080/10717544.2025.2586305
J Nanobiotechnology. 2025 Dec 13.

Engineered extracellular vesicles-mediated curcumin delivery in brain microenvironment modulating lysosomes, mitochondria, and microglia reprogram for parkinson's disease therapy.

Ming-You Shie, Mei-Chih Chen, Yeh Chen, Shi-Wei Huang, Yen-Hong Lin, Min-Hua Yu, Chih-Ming Pan, Cheng-Yu Chen, Yi-Wen Chen, Ching-Liang Hsieh, Shao-Chih Chiu, Shung-Te Kao, Jaung-Geng Lin, Der-Yang Cho.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, aggregation of α-synuclein (α-Syn), lysosomal dysfunction, and mitochondrial impairment. Curcumin has demonstrated neuroprotective effects against PD pathology; however, its poor bioavailability, rapid systemic clearance, and limited blood-brain barrier permeability remain significant challenges to be overcome. An extracellular vesicle (EV)-based dopamine transporter (DAT)-targeted drug delivery system, derived from genetically engineered HEK293T cells, expressing DAT-targeting single-chain variable fragments (scFv) on the EV surface, is developed. Curcumin is encapsulated into the DAT-targeting EVs (αDAT EVs) for precise delivery into dopaminergic neurons. In the PD cell model, significant EV uptake is observed, with a reduced accumulation of α-Syn, alongside restored expression of DJ-1, TH, and PARKIN following treatment with curcumin-loaded DAT-targeting EVs (Cur@αDAT EVs). In a 6-hydroxydopamine (6-OHDA)-induced PD rat model, Cur@αDAT EVs significantly enhanced motor and cognitive function, protected dopaminergic neurons, and attenuated neuroinflammation, with microglial activation considered a downstream paracrine/bystander effect following neuronal rescue. Accumulation of curcumin in the substantia nigra and ventral tegmental area confirms precise αDAT-EV-mediated delivery, addressing the pharmacokinetic challenges of free curcumin. Overall, DAT-targeting EVs represent a promising precision delivery platform for combating PD.

Keywords:  Curcumin; Dopamine transporter; Extracellular vesicles; Parkinson’s disease; Targeted drug delivery

DOI:  https://doi.org/10.1186/s12951-025-03911-z
Biomater Res. 2025 ;29 0284

Bioengineered Anti-PD-L1 Functionalized Nanoplatform for Targeted Delivery and Tumor Immune Reprogramming Against Colorectal Cancer.

Miao Liu, Xinjuan Ma, Ruijie Zhou, Xiaojuan Yang, Yongsheng Zhou, Bin Ma, Chunxia Su, Xiangguo Duan.

Colorectal cancer (CRC) remains a major clinical challenge owing to its immunosuppressive tumor microenvironment and limited targeting therapeutic efficiency. Developing innovative strategies that integrate immune activation with enhanced tumor-targeting ability is urgently needed. Herein, we reported a bioengineered exosome drug delivery nanoplatform (Apatinib-ExoaPD-L1), in which HEK293T-derived exosomes were surface functionalized with anti-PD-L1 antibody (aPD-L1) and encapsulated the tyrosine kinase inhibitor Apatinib, aiming to enhance the tumor-targeted immunotherapy against CRC. Apatinib-ExoaPD-L1 exhibited efficient tumor-targeting capability and prolonged systemic circulation, attributed to aPD-L1 modification, resulting in markedly enhanced antitumor efficacy without evident body toxicity. Mechanistically, Apatinib was efficiently delivered and internalized by tumor cells, where it triggered immunogenic cell death (ICD) and promoted dendritic cell maturation. This immune activation cascade facilitated the infiltration and activation of cytotoxic T cells within the tumor microenvironment. Furthermore, Apatinib-ExoaPD-L1 reduced the population and suppressive function of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thereby effectively reversing immune suppression and amplifying the antitumor immune response. Collectively, our findings demonstrated that Apatinib-ExoaPD-L1 is a safe and effective exosome-based therapeutic platform, offering a promising strategy to convert immunologically "cold" tumors into "hot" ones and improve clinical outcomes in CRC.

DOI: https://doi.org/10.34133/bmr.0284
Brain Res. 2025 Dec 13. pii: S0006-8993(25)00675-4. [Epub ahead of print] 150112

GPX4-overexpressing mesenchymal stem cell-derived exosomes ameliorate secondary brain injury after intracerebral hemorrhage by inhibiting neuronal ferroptosis.

Yini Wu, Weifeng Shan, Xin Han, Hong Dai, Ruijun Ma, Jimin Wu.

  Closely linked to intracerebral hemorrhage (ICH)-related secondary brain injury, ferroptosis lacks effective treatments, whereas exosomes offer novel neuroprotective potential. This study aimed to investigate the neuroprotective effects and mechanisms of exosomes derived from bone marrow mesenchymal stem cells overexpressing glutathione peroxidase 4 (exo-GPX4) in ICH. In in vitro experiments, exo-GPX4 were constructed and exosomes were extracted using ultracentrifugation, followed by characterization through transmission electron microscopy, nanoparticle tracking analysis, and Western blot. In a hemin-induced HT22 cell injury model, cell viability was detected by CCK-8 assay, apoptosis was analyzed by flow cytometry, and Fe2+, MDA, and GSH levels were measured by colorimetric assay, and the expression levels of GPX4, ACSL4, and SLC7A11 proteins were detected by Western blot. In vivo experiments, an ICH rat model was established, and histopathological changes were assessed through neurological function scores, H&E staining, Prussian blue staining, and TUNEL assay. Serum ferroptosis-related indicators were detected using kits, while Western blot and immunofluorescence were employed to examine the expression levels of GPX4, ACSL4, and SLC7A11 proteins and the localization of GPX4, respectively. The results demonstrated that in vitro, exo-GPX4 significantly enhanced cell viability, reduced apoptosis, decreased Fe2+ and MDA levels, and increased GSH content. In vivo, exo-GPX4 treatment markedly improved neurological function scores, alleviated cerebral iron deposition and neuronal apoptosis, and modulated serum ferroptosis-related indicators. Mechanistic studies revealed that exo-GPX4 upregulates GPX4 and SLC7A11 protein expression while downregulating ACSL4 expression. In conclusion, exo-GPX4 mitigates secondary brain injury after ICH by inhibiting ferroptosis, revealing a novel therapeutic strategy.

Keywords:  Exosomes; Ferroptosis; GPX4; Intracerebral hemorrhage; Mesenchymal stem cells

DOI:  https://doi.org/10.1016/j.brainres.2025.150112
Front Pharmacol. 2025 ;16 1682468

Gentamicin-loaded exosomes from IMMUNEPOTENT CRP enhance healing of infected diabetic wound in mice.

Paola Leonor García Coronado, Brandon Alberto Garza Martínez, Kenia Arisbe Moreno Amador, David Reding Hernández, Diana G Zárate Triviño, Diana Elia Caballero Hernández, Pablo Zapata Benavides, Gabriel Luna Barcenas, Cristina Rodríguez-Padilla, Moisés Armides Franco Molina.

   Introduction: Diabetic foot infections (DFIs) are a major cause of lower extremity amputations and are associated with substantial morbidity and reduced quality of life. Given the limited efficacy of current treatments and the rise of antimicrobial resistance, there is an urgent need for innovative therapeutic approaches. This study evaluates the use of exosomes derived from a bovine leukocyte spleen extract (IMMUNEPOTENT CRP), loaded with gentamicin, to improve infection control and promote wound healing in a diabetic setting.
Methods: The efficiency of gentamicin encapsulation were evaluated followed by gentamicin release under acidic and alkaline conditions. A wound model was established in streptozotocin (STZ)-induced diabetic mice, followed by inoculation with Staphylococcus aureus to simulate infected diabetic ulcers. Mice were treated with gentamicin-loaded exosomes (Exo-Genta), IMMUNEPOTENT CRP-derived exosomes (ICRP-Exo), or free gentamicin. Wound closure was assessed for 21 days. On days 0, 7, 14, and 21 skin tissue samples were collected from treated mice to evaluate epithelial thickness, area, and cell number calculation by hematoxylin and eosin (H&E); collagen synthesis, and PI3K-AKT pathway activation, beside skin samples, blood samples were collected to quantify pro-inflammatory cytokine levels.
Results: The Exo-Genta and IMMUNEPOTENT CRP significantly enhanced collagen fiber deposition, blood vessel formation, and hair follicle regeneration. At the molecular level, these treatments increased AKT phosphorylation and modulated the inflammatory response, with reduced levels of TNF-α, IL-6, and MCP-1, alongside a significant increase in anti-inflammatory IL-10.
Conclusions: Gentamicin-loaded exosomes derived from IMMUNEPOTENT CRP demonstrated enhanced antimicrobial activity and tissue regeneration in infected diabetic wounds. These findings support their potential as an effective and less invasive therapeutic strategy for diabetic foot ulcers by combining infection control and pro-regenerative and immunomodulatory effects.

Keywords:  IMMUNEPOTENT CRP; diabetic ulcer; exosomes; gentamicin; regenerative; wound healing

DOI:  https://doi.org/10.3389/fphar.2025.1682468
J Extracell Vesicles. 2025 Dec;14(12): e70201

Hybrid Extracellular Vesicles for Efficient Loading and Functional Delivery of mRNA.

Xiaoqin Wang, Michael J Munson, Kristina Friis, Anna Marzeda, Andreia M Silva, Franziska Kohl, Leif Hultin, Raymond M Schiffelers, Niek Dekker.

  Extracellular vesicles (EVs) are an attractive delivery vehicle with biological activity, intrinsic homing, low immunogenicity, and engineerability; however, challenges remain regarding loading and functional delivery of mRNA. Here, we developed a novel approach to load mRNA through low pH-induced fusion of EVs with lipid nanoparticles (LNPs) to generate hybrid EVs (HEVs). Conventional characterization showed that HEVs preserved classical features of EVs. Single particle analysis revealed successful loading of mRNA and incorporation of LNP components into HEVs. The combined properties from EV and LNP contributed to the excellent cell tolerability of HEV, overcoming dose-limit toxicity, and functional delivery of mRNA by HEV. We further elucidated the mechanism of HEV-mediated intracellular delivery of mRNA. Our results showed that in contrast to source EVs, HEVs were capable of inducing endosomal escape, facilitating intracellular delivery of mRNA. Furthermore, HEVs functionally delivered mRNA in vivo and displayed extrahepatic delivery capacity with predominant functional distribution in spleen. Our results suggest HEVs as a promising EV-based delivery platform for mRNA delivery.

Keywords:  cell tolerability; endosomal escape; functional biodistribution; functional delivery; hybrid extracellular vesicle; mRNA loading

DOI:  https://doi.org/10.1002/jev2.70201
Biomed Pharmacother. 2025 Dec 12. pii: S0753-3322(25)01097-2. [Epub ahead of print]194 118903

Exosome-mediated scutellarin delivery enhances BBB penetration and microglia targeting in antiviral neuroprotection.

Chunlian Song, Shengjia Sun, Ting Li, Ke Zhang, Xiong Zhao, Zee Zhu, Deng Pan, Huayi Bai, Ying Zhang, Deyan Cui, Limei Yang, Xiaoyu Liu, Xianghua Shu.

  Scutellarin, the active component of Erigeron breviscapus(Vant.)Hand.-Mazz, has therapeutic potential for neurological diseases but is limited by poor solubility, low bioavailability, and inability to cross the blood-brain barrier (BBB). This study used mouse brain tissue-derived exosomes as a delivery system for scutellarin. Exosomes were isolated via ultracentrifugation and loaded with scutellarin using ultrasonication, achieving a drug loading capacity of 31.86 ng/μg and a particle size of 90-120 nm. In an in vitro BBB model, exosome-loaded scutellarin showed significantly higher penetration (41 %) than the free drug (13.5 %). Confocal microscopy confirmed efficient cellular uptake, particularly by microglia (98 % efficiency). In vivo, exosomes accumulated and persisted in brain tissue for over 24 h. In a PRV-infected microglia model, exosome-delivered scutellarin significantly inhibited viral replication and modulated microglial polarization by downregulating the pro-inflammatory marker CD86 and upregulating the anti-inflammatory marker CD206. These findings demonstrate that brain-derived exosomes enhance scutellarin delivery across the BBB and improve its anti-neuroinflammatory effects, supporting their use as drug carriers for treating neuroinflammatory diseases.

Keywords:  Blood-brain barrier; Drug delivery; Exosomes; Microglial polarization; Scutellarin

DOI:  https://doi.org/10.1016/j.biopha.2025.118903
J Extracell Vesicles. 2025 Dec;14(12): e70199

Targeted Intracellular Delivery via Precision Programming of ARRDC1-Mediated Microvesicles.

Zhi Qiao, Sengjin Choi, Zunwei Chen, Roland Mason Rodriguez, Qiyu Wang, Zhiping Yang, Samuel A Theuerkauf, Joseph F Nabhan, Takao K Hensch, Christian J Buchholz, Quan Lu.

  Efficient and cell-specific delivery remains a major barrier to realising the full therapeutic potential of modalities such as mRNA and CRISPR-based gene editors. Here, we report a versatile delivery platform based on engineered ARRDC1-mediated microvesicles (ARMMs) capable of delivering cargo to defined cell populations. By decorating ARMMs with engineered Nipah virus (NiV)-derived fusion and attachment proteins conjugated to cell-specific ligands, we enable selective binding and membrane fusion-mediated cargo release. ARMMs functionalized with anti-CD8 single-chain variable fragment (scFv) delivered protein, mRNA, or CRISPR-Cas9 base editor selectively to CD8⁺ T cells. Similarly, ARMMs displaying a designed ankyrin repeat protein (DARPin) targeting the GluA4 receptor enabled delivery to parvalbumin-positive (PV⁺) neurons. In vivo, administration of targeted ARMMs resulted in functional delivery to CD8⁺ splenocytes and PV⁺ cortical neurons in mice. These findings establish surface-engineered ARMMs as a programmable and modular system for precision delivery of therapeutic macromolecules, with broad applicability in gene and RNA-based medicine.

Keywords:  ARMMs; mRNA and CRISPR therapeutics; non‐viral delivery; precision medicine; targeted delivery

DOI:  https://doi.org/10.1002/jev2.70199
ACS Appl Bio Mater. 2025 Dec 16.

Engineered Plant-Derived Extracellular Vesicles as Targeted Drug Carriers in Cancer Therapy.

Su Jin Kang, Won Jong Rhee.

  Breast cancer remains one of the most prevalent and deadly cancers worldwide, with many patients experiencing limited treatment efficacy and adverse side effects from conventional chemotherapy. These limitations are primarily due to poor drug targeting, low bioavailability, and systemic toxicity. To address these challenges, extracellular vesicles (EVs) have emerged as promising drug delivery systems owing to their innate biocompatibility, cellular delivery capabilities, and ability to carry diverse bioactive molecules. Among various EV sources, plant-derived EVs offer unique advantages, including low immunogenicity, cost-effective scalability, and absence of animal-derived components, making them highly suitable for clinical applications. In this study, we developed a plant-derived EV-based drug delivery platform using black soybean-derived extracellular vesicles (Blex). A high yield of Blex was successfully purified from black soybean and subsequently loaded with a substantial amount of chemotherapeutic agent doxorubicin (Dox) through passive diffusion. To achieve tumor-targeting specificity, Blex were chemically engineered by covalently conjugating the cyclic RGD (cRGD) peptide, which binds to integrin receptors overexpressed in many cancer types, including breast cancer. The resulting Dox-loaded Blex engineered with cancer cell-targeting cRGD (Blex(Dox)_cRGD) demonstrated enhanced cellular uptake, improved cytotoxicity against breast cancer cells, and greater tumor reduction in vivo. This work highlights the potential of combining drug loading with surface engineering to improve therapeutic outcomes while minimizing systemic toxicity. Overall, our findings underscore the utility of plant-derived EVs as a scalable, biocompatible platform for targeted chemotherapy. This strategy provides a foundation for next-generation nanomedicine development, offering a therapeutic approach for breast cancer and other solid tumors.

Keywords:  black soybean-derived extracellular vesicles; cancer therapy; drug delivery; extracellular vesicles; plant-derived extracellular vesicles

DOI:  https://doi.org/10.1021/acsabm.5c01943