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Pharmaceutics
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Extracellular Vesicles for Targeted Delivery
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Extracellular Vesicles for Targeted Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 9225

Special Issue Editor

Dr. Beáta Soltész

E-Mail Website
Guest Editor
Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
Interests: clinical application of liquid biopsy; exosomes; nucleic acids (e.g., gDNA, mtDNA, miRNA, and lncRNA) and cell-free nucleic acids; molecular biology; genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs), mainly exosomes, are more applicable in the early detection, characterization, and monitoring of various diseases. EVs are packed with several molecules, which may affect cell-to-cell communication after release. Therefore, these are ideal candidates for delivering molecules such as nucleic acids, proteins, and designed drugs. The modified and engineered exosomes may become star delivery vehicles and the importance of these in therapy may be highlighted. We may gather worthwhile information from EVs to understand their role in the progression of distinct diseases and in treatment options as carrying cargo to the target cells. Several beneficial properties of EVs make them promising therapeutic shuttle vesicles, and therefore, personalized medicine made from engineered extracellular vesicles may be a new treatment option for various diseases.

This Special Issue aims to address the latest research or new views on extracellular vesicles in the monitoring, characterizing, and understanding of background mechanisms, and thus, possible therapeutic applications.

Dr. Beáta Soltész
Guest Editor

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Keywords

  • computational approaches
  • drug delivery
  • engineered exosomes
  • exosomes
  • experimental approaches
  • extracellular vesicle-based delivery
  • extracellular vesicles
  • immunotherapy
  • nanomedicine
  • therapeutic cargo
  • therapy

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Published Papers (6 papers)

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Research

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21 pages, 2523 KB  
Article
Extracellular Vesicles from Osteotropic Triple-Negative Breast Cancer Cells Transfer miRNAs to Bone Cells Reducing Collagen Expression and Bone Matrix Mineralisation
by Luca Giacchi, Argia Ucci, Elisa Pucci, Loreto Lancia, Fanny Pulcini, Simona Delle Monache, Nadia Rucci and Marco Ponzetti
Pharmaceutics 2026, 18(3), 317; https://doi.org/10.3390/pharmaceutics18030317 - 2 Mar 2026
Viewed by 848
Abstract
Background/Objectives: Bone metastases are a common complication of breast cancer. In our previous study, we reported that extracellular vesicles released by osteotropic human (MDA-MB-231) and murine (4T1) breast cancer cells disrupt bone homeostasis by enhancing osteoclast differentiation and impairing osteoblast function. Based [...] Read more.
Background/Objectives: Bone metastases are a common complication of breast cancer. In our previous study, we reported that extracellular vesicles released by osteotropic human (MDA-MB-231) and murine (4T1) breast cancer cells disrupt bone homeostasis by enhancing osteoclast differentiation and impairing osteoblast function. Based on these findings, we investigated whether microRNAs contained within tumour-derived EVs could mediate these bone-altering effects. Methods: MDA-MB-231- and 4T1-EVs were tagged with the RNA-specific fluorophore SYTORNA and employed to treat mouse primary bone marrow macrophages (BMMs) and osteoblasts (OBs). We also performed RNAseq on MDA-MB-231- and 4T1-EVs to assess their miRNAs content. Finally, we evaluated the effect of selected miRNA-mimics on OBs, BMMs and HUVEC cells. Results: Fluorescence microscopy demonstrated EV-RNAs shuttling to recipient cells, while RNA sequencing on MDA-MB-231- and 4T1-EVs revealed that, of the top 20 expressed miRNAs, 10 were common. Among them, we first focused on the following four: miR-26a-5p, miR-24-3p, miR-29a-3p, and miR-29b-3p, which were linked to bone biology. We confirmed their presence in MDA-MB-231-/4T1-EVs by qPCR. Then, we evaluated their EV-mediated shuttling to BMMs and OBs using affinity tags. Among all the conditions tested, miR-29a and miR-29b were the best-shuttled miRNAs, with efficiency between 50–100% in both OBs and BMMs, both for MDA-MB-231- and 4T1-EVs. Finally, to test whether miR-29a and miR-29b could have a functional role in bone cells, OBs were transfected with miR-29a and 29b-mimics, discovering that this treatment reduced collagen1α1 and 1α2 mRNA as well as the OBs’ mineralisation ability, while the same miRNA mimics were found to have no effect on osteoclastogenesis or on in vitro angiogenesis. Conclusions: MDA-MB-231- and 4T1-EVs shuttle miRNAs to bone cells, which likely contributes to OBs’ activity impairment. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)
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19 pages, 4023 KB  
Article
Hacking Extracellular Vesicles: Using Vesicle-Related Tags to Engineer Mesenchymal Stromal Cell-Derived Extracellular Vesicles
by Gabriele Scattini, Giulia Pianigiani, Stefano Capomaccio, Maria Rachele Ceccarini, Samanta Mecocci, Laura Musa, Luca Avellini, Olimpia Barbato, Antonello Bufalari, Patrizia Casagrande Proietti, Rodolfo Gialletti, Alessia Sulla, Tommaso Beccari and Luisa Pascucci
Pharmaceutics 2025, 17(11), 1435; https://doi.org/10.3390/pharmaceutics17111435 - 6 Nov 2025
Cited by 1 | Viewed by 976
Abstract
Background/Objectives: Extracellular Vesicles (EVs) have shown great promise as diagnostic and therapeutic tools, as well as pharmacological nanocarriers. Various strategies are being explored to develop EVs for monitoring, imaging, loading with pharmacological agents, and surface decoration with tissue-specific ligands. EVs derived from [...] Read more.
Background/Objectives: Extracellular Vesicles (EVs) have shown great promise as diagnostic and therapeutic tools, as well as pharmacological nanocarriers. Various strategies are being explored to develop EVs for monitoring, imaging, loading with pharmacological agents, and surface decoration with tissue-specific ligands. EVs derived from Mesenchymal Stromal Cells (MSC-EVs) are of particular interest both as therapeutics per se and as natural nanocarriers for the targeted delivery of biotherapeutics. Methods: In this study, we investigated the ability of different tags to deliver a reporter protein into canine MSC-EVs with the aim of identifying the most effective endogenous loading mechanism. To this aim, canine MSCs were engineered to express the Green Fluorescent Protein (GFP) fused to CD63, Syntenin-1, TSG101, and the palmitoylation signal of Lck, which were expected to promote GFP incorporation into EVs. Overexpression of tagged GFP in canine MSCs was confirmed by Western blotting and examined by confocal microscopy and transmission electron microscopy to map intracellular localization. Results: All tags were able to deliver GFP into EVs. Syntenin-1 showed relatively high loading efficiency and secretion index but exhibited a diffuse localization pattern in the transfected cells. The palmitoylation signal showed low loading efficiency and localization specificity. TSG101 displayed a morphological pattern consistent with specific localization in endosomal structures, but its low expression level prevented further evaluations. Finally, CD63 showed the highest expression efficiency, as GFP-CD63 levels were approximately 5-fold higher than untagged GFP. Conclusions: In conclusion, CD63 emerged as the most suitable tag for canine MSC-EV engineering. Indeed, even if the secretion index favours Syntenin-1, CD63’s higher abundance in the lysate suggests its substantial post-secretion uptake. Further studies aimed at elucidating CD63’s specific contribution and identifying the domains involved in vesicle trafficking could provide valuable insights into EV bioengineering. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)
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27 pages, 6020 KB  
Article
Engineered Nanobody-Bearing Extracellular Vesicles Enable Precision Trop2 Knockdown in Resistant Breast Cancer
by Jassy Mary S. Lazarte, Mounika Aare, Sandeep Chary Padakanti, Arvind Bagde, Aakash Nathani, Zachary Meeks, Li Sun, Yan Li and Mandip Singh
Pharmaceutics 2025, 17(10), 1318; https://doi.org/10.3390/pharmaceutics17101318 - 11 Oct 2025
Cited by 2 | Viewed by 1667
Abstract
Background/Objectives: Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in a broad spectrum of epithelial malignancies but minimally expressed in normal tissues, has emerged as a clinically relevant prognostic biomarker and therapeutic target, particularly in breast cancer. This study aims [...] Read more.
Background/Objectives: Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in a broad spectrum of epithelial malignancies but minimally expressed in normal tissues, has emerged as a clinically relevant prognostic biomarker and therapeutic target, particularly in breast cancer. This study aims to develop an enhanced way of targeting Trop2 expression in tumors and blocking it using extracellular vesicles (EVs) bioengineered to express a nanobody sequence against Trop2 (NB60 E). Methods: Here, a plasmid construct was designed to express the Trop2 sequence, NB60, flanked with HA tag and myc epitope and a PDGFR transmembrane domain in the C-terminal region, and was transfected into HEK293T cells for EVs isolation. The potency of NB60 E to knock down Trop2 in letrozole-resistant breast cancer cells (LTLT-Ca and MDA-MB-468 cells) was initially investigated. Thereafter, the effects of NB60 E on the cell viability and downstream signaling pathway of Trop2 via MTT assay and Western blotting were determined. Lastly, we also examined whether NB60 E treatment in Jurkat T cells affects IL-6, TNF-α, and IL-2 cytokine production by enzyme-linked immunosorbent assay (ELISA). Results: Results revealed treatment with NB60 E significantly reduced surface Trop2 expression across both cell lines by 23.5 ± 1.5% in MDA-MB-468, and 61.5 ± 1.5% in LTLT-Ca, relative to the HEK293T-derived control EVs (HEK293T E). NB60 E treatment resulted in a marked reduction in LTLT-Ca cell viability by 52.8 ± 0.9% at 48 h post-treatment. This was accompanied by downregulation of key oncogenic signaling molecules: phosphorylated ERK1/2 (p-ERK 1/2) decreased by 30 ± 4%, cyclin D1 by 67 ± 11%, phosphorylated STAT3 (p-STAT3) by 71.8 ± 1.6%, and vimentin by 40.8 ± 1.4%. ELISA analysis revealed significant decreases in IL-6 (−57.5 ± 1.5%, 7.4 ± 0.35 pg/mL) and TNF-α (−32.1 ± 0.3%, 6.1 ± 1.2 pg/mL) levels, coordinated by an increase in IL-2 secretion (22.1 ± 2.7%, 49.2 ± 1.1 pg/mL). Quantitative analysis showed marked reductions in the number of nodes (−45 ± 4.4%), junctions (−55 ± 3.5%), and branch points (−38 ± 1.2%), indicating suppression of angiogenic capacity. In vivo experiment using near-infrared Cy7 imaging demonstrated rapid and tumor-selective accumulation of NB60 E within 4 h post-administration, followed by efficient systemic clearance by 24 h. The in vivo results demonstrate the effectiveness of NB60 E in targeting Trop2-enriched tumors while being efficiently cleared from the system, thus minimizing off-target interactions with normal cells. Lastly, Trop2 expression in LTLT-Ca tumor xenografts revealed a significant reduction of 41.0 ± 4% following NB60 E treatment, confirming efficient targeted delivery. Conclusions: We present a first-in-field NB60 E-grafted EV therapy that precisely homes to Trop2-enriched breast cancers, silences multiple growth-and-invasion pathways, blocks angiogenesis, and rewires cytokine crosstalk, achieving potent antitumor effects with self-clearing, biomimetic carriers. Our results here show promising potential for the use of NB60 E as anti-cancer agents, not only for letrozole-resistant breast cancer but also for other Trop2-expressing cancers. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)
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Review

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32 pages, 14136 KB  
Review
Advances of Cell Membrane-Coated Nanotechnology and Membrane Vesicles in Intestinal Targeted Drug Delivery Systems
by Rou Tang, Fujun Zeng, Chengzhen Lyu, Jianyekai Tuerheng, Ziqi Guo, Kun He and Dong Wu
Pharmaceutics 2026, 18(5), 534; https://doi.org/10.3390/pharmaceutics18050534 - 27 Apr 2026
Viewed by 632
Abstract
Although nanomedicine has enabled significant advances in drug delivery, the clinical translation of conventional synthetic nanocarriers is limited by immune clearance, non-specific biodistribution, and gastrointestinal instability. This poses major challenges for therapy targeting the intestines. Cell membrane-coated nanotechnology (CMCT) and membrane vesicle-based systems [...] Read more.
Although nanomedicine has enabled significant advances in drug delivery, the clinical translation of conventional synthetic nanocarriers is limited by immune clearance, non-specific biodistribution, and gastrointestinal instability. This poses major challenges for therapy targeting the intestines. Cell membrane-coated nanotechnology (CMCT) and membrane vesicle-based systems have emerged as biomimetic platforms integrating synthetic nanomaterials with naturally derived biological interfaces. These biohybrid systems inherit biological functions originating from cells, including immune evasion, prolonged circulation, lesion homing, and microenvironment-responsive interactions, through the direct transfer of intact membrane components. This review summarizes recent advances in CMCT and membrane vesicle-based strategies for intestinal drug delivery. It covers fabrication methodologies, programmable manufacturing approaches, and functional regulation enabled by diverse membrane sources and hybrid engineering designs. Applications in inflammatory bowel disease, colorectal cancer, and intestinal infections are highlighted, emphasizing key therapeutic mechanisms, such as targeting inflammation, neutralizing toxins, modulating the immune system, and regulating the microbiome. We also discuss the major challenges of translation, such as preserving membrane and coating integrity, ensuring oral stability, achieving batch reproducibility, and ensuring biosafety. Overall, this review establishes a conceptual and engineering framework to guide the transition of membrane-based nanocarriers from passive biomimicry to adaptive, clinically translatable intestinal delivery systems. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)
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20 pages, 705 KB  
Review
Corneal Extracellular Vesicles: Small Packages with a Big Impact
by Brenna S. Hefley, Pawan Shrestha, Tina B. McKay, Peter Nsiah, Yasamin Moradi, Sarah E. Nicholas and Dimitrios Karamichos
Pharmaceutics 2026, 18(2), 186; https://doi.org/10.3390/pharmaceutics18020186 - 31 Jan 2026
Viewed by 1001
Abstract
Extracellular vesicles (EVs) are small membrane-bound particles that play a vital role in intercellular communication by facilitating the transfer of molecular cargo. In this review, we provide an overview of EV biology in corneal diseases, along with current approaches to therapeutic uses of [...] Read more.
Extracellular vesicles (EVs) are small membrane-bound particles that play a vital role in intercellular communication by facilitating the transfer of molecular cargo. In this review, we provide an overview of EV biology in corneal diseases, along with current approaches to therapeutic uses of EVs. Since EVs generally retain surface markers indicative of their cell of origin, they possess a degree of tissue specificity, which benefits drug delivery systems and highlights their potential as biomarkers to study disease processes. Further advances in technology and methodology will accelerate our understanding of EVs and help guide the field towards improved diagnostic techniques and therapeutic targets. We summarize EVs and their potential impact in medicine with a discussion of the limitations that remain in current approaches, as well as areas to focus on for future growth. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)
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22 pages, 1826 KB  
Review
Nanomanaging Chronic Wounds with Targeted Exosome Therapeutics
by Anita Yadav, Anu Sharma, Mohini Moulick and Subhadip Ghatak
Pharmaceutics 2025, 17(3), 366; https://doi.org/10.3390/pharmaceutics17030366 - 13 Mar 2025
Cited by 8 | Viewed by 3263
Abstract
Chronic wounds pose a significant healthcare challenge, impacting millions of patients worldwide and burdening healthcare systems substantially. These wounds often occur as comorbidities and are prone to infections. Such infections hinder the healing process, complicating clinical management and proving recalcitrant to therapy. The [...] Read more.
Chronic wounds pose a significant healthcare challenge, impacting millions of patients worldwide and burdening healthcare systems substantially. These wounds often occur as comorbidities and are prone to infections. Such infections hinder the healing process, complicating clinical management and proving recalcitrant to therapy. The environment within the wound itself poses challenges such as lack of oxygen, restricted blood flow, oxidative stress, ongoing inflammation, and bacterial presence. Traditional systemic treatment for such chronic peripheral wounds may not be effective due to inadequate blood supply, resulting in unintended side effects. Furthermore, topical applications are often impervious to persistent biofilm infections. A growing clinical concern is the lack of effective therapeutic modalities for treating chronic wounds. Additionally, the chemically harsh wound microenvironment can reduce the effectiveness of treatments, highlighting the need for drug delivery systems that can deliver therapies precisely where needed with optimal dosages. Compared to cell-based therapies, exosome-based therapies offer distinct advantages as a cell-free approach for chronic wound treatment. Exosomes are of endosomal origin and enable cell-to-cell communications, and they possess benefits, including biocompatibility and decreased immunogenicity, making them ideal vehicles for efficient targeting and minimizing off-target damage. However, exosomes are rapidly cleared from the body, making it difficult to maintain optimal therapeutic concentrations at wound sites. The hydrogel-based approach and development of biocompatible scaffolds for exosome-based therapies can be beneficial for sustained release and prolong the presence of these therapeutic exosomes at chronic wound sites. Engineered exosomes have been shown to possess stability and effectiveness in promoting wound healing compared to their unmodified counterparts. Significant progress has been made in this field, but further research is essential to unlock their clinical potential. This review seeks to explore the benefits and opportunities of exosome-based therapies in chronic wounds, ensuring sustained efficacy and precise delivery despite the obstacles posed by the wound environment. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)
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