---
title: "Dual‑Targeted M1 Macrophage Extracellular Vesicles Boost NK Cell Immunotherapy in Breast Cancer"
id: "pubmed-42814771"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42814771"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42814771/"
doi: "10.1002/jev2.70379"
published_at: "2026-10-01T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Dual‑Targeted M1 Macrophage Extracellular Vesicles Boost NK Cell Immunotherapy in Breast Cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42814771
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42814771/)
- **DOI:** [10.1002/jev2.70379](https://doi.org/10.1002%2Fjev2.70379)
- **Published At:** 2026-10-01T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study describes a novel immunotherapeutic platform using **M1 macrophage extracellular vesicles** modified with **hyaluronic acid (HA)** and cyclic RGD peptide (cRGD), termed M1EV_HA/cRGD. - M1EV_HA/cRGD are designed to act as molecular bridges that physically link **natural killer (NK) cells)** to breast cancer cells through dual targeting: HA engages **CD44** on NK cells and cRGD binds tumor-overexpressed integrins. - The vesicles deliver inflammatory cytokines and miRNAs from pro-inflammatory M1 macrophages, intended to reprogram the immunosuppressive **tumor microenvironment (TME)** into a pro-inflammatory state. - In vitro and in vivo experiments reported in the article demonstrate increased NK cell clustering at tumor sites, elevated NK activation status, and enhanced cytotoxic killing of breast cancer cells when combined with M1EV_HA/cRGD. - The authors contrast this **dual-targeted** approach with single-targeted strategies, noting it simultaneously promotes TME reprogramming and stronger immune–tumor engagement. - The platform is presented as a potential solution to therapeutic resistance and treatment failure in advanced or recurrent breast cancer by amplifying innate antitumor immunity. - Keywords and focus areas include breast cancer immunotherapy, extracellular vesicles, NK cells, tumor microenvironment, hyaluronic acid, and cRGD. - Publication details: Su Jin Kang et al., J Extracell Vesicles. 2026 Oct;15(10):e70379. PMID 42814771; DOI 10.1002/jev2.70379.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea. * 2 Division of Bioengineering, Incheon National University, Incheon, South Korea. * 3 Research Center for Bio Materials & Process Development, Incheon National University, Incheon, South Korea. * 4 Integrated Major in Bio-manufacturing AX, Incheon National University, Incheon, South Korea. # Contributed equally. * PMID: **42814771** * DOI: [ 10.1002/jev2.70379 ](https://doi.org/10.1002/jev2.70379) Item in Clipboard # Dual-Targeted M1 Macrophage Extracellular Vesicles Reprogram the Tumor Microenvironment and Enhance Natural Killer Cell Immunotherapy in Breast Cancer Su Jin Kang et al. J Extracell Vesicles. 2026 Oct. Show details Display options Display options Format Abstract PubMed PMID J Extracell Vesicles Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22J+Extracell+Vesicles%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22J+Extracell+Vesicles%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) . 2026 Oct;15(10):e70379. doi: 10.1002/jev2.70379. ### Authors [Su Jin Kang](https://pubmed.ncbi.nlm.nih.gov/?term=Kang+SJ&cauthor_id=42814771)[#](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-1 "Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea."), [Gichan Baek](https://pubmed.ncbi.nlm.nih.gov/?term=Baek+G&cauthor_id=42814771)[#](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-1 "Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-2 "Division of Bioengineering, Incheon National University, Incheon, South Korea."), [Suwun Ju](https://pubmed.ncbi.nlm.nih.gov/?term=Ju+S&cauthor_id=42814771)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-1 "Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-2 "Division of Bioengineering, Incheon National University, Incheon, South Korea."), [Gunhee Kim](https://pubmed.ncbi.nlm.nih.gov/?term=Kim+G&cauthor_id=42814771)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-1 "Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-2 "Division of Bioengineering, Incheon National University, Incheon, South Korea."), [Seongjin Gwak](https://pubmed.ncbi.nlm.nih.gov/?term=Gwak+S&cauthor_id=42814771)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-1 "Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-2 "Division of Bioengineering, Incheon National University, Incheon, South Korea."), [Won Jong Rhee](https://pubmed.ncbi.nlm.nih.gov/?term=Rhee+WJ&cauthor_id=42814771)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-1 "Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-2 "Division of Bioengineering, Incheon National University, Incheon, South Korea.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-3 "Research Center for Bio Materials & Process Development, Incheon National University, Incheon, South Korea.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42814771/#short-view-affiliation-4 "Integrated Major in Bio-manufacturing AX, Incheon National University, Incheon, South Korea.") ### Affiliations * 1 Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, South Korea. * 2 Division of Bioengineering, Incheon National University, Incheon, South Korea. * 3 Research Center for Bio Materials & Process Development, Incheon National University, Incheon, South Korea. * 4 Integrated Major in Bio-manufacturing AX, Incheon National University, Incheon, South Korea. # Contributed equally. * PMID: **42814771** * DOI: [ 10.1002/jev2.70379 ](https://doi.org/10.1002/jev2.70379) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Breast cancer is the most commonly diagnosed cancer worldwide and a leading cause of cancer-related mortality in women. Despite therapeutic advances, treating advanced or recurrent cases is substantially hampered by drug resistance and the immunosuppressive tumor microenvironment (TME). Here, we report a breakthrough immunotherapeutic strategy using dual-targeted extracellular vesicles from pro-inflammatory M1 macrophages, hyaluronic acid (HA), and cyclic RGD (M1EV_HA/cRGD), which function as molecular bridges to physically link natural killer (NK) cells with cancer cells. Our platform simultaneously reprograms the hostile TME while activating potent antitumor immunity. HA is incorporated to engage CD44 receptors on NK cells and cRGD peptides to bind tumor-overexpressing integrins, establishing precision dual-targeting. M1EV_HA/cRGD could physically tether NK cells directly to tumors, and deliver inflammatory cytokines and miRNAs that transform the immunosuppressive TME into a pro-inflammatory battlefield, substantially amplifying immune activation. In vitro and in vivo studies demonstrate that M1EV_HA/cRGD significantly enhances NK cell clustering at tumor sites, activation status, and cytotoxic killing of breast cancer cells. Unlike single-targeted approaches, this dual-targeting mechanism achieves simultaneous TME reprogramming and enhanced immune-tumor engagement. M1EV_HA/cRGD is a paradigm shift in solid tumor immunotherapy that directly addresses breast cancer treatment failure, can overcome therapeutic resistance, and substantially improve patient survival outcomes. **Keywords:** breast cancer immunotherapy; dual‐targeted; extracellular vesicles; natural killer cell; tumor microenvironment. © 2026 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## References 1. 1. Anderson, N. M., and M. C. Simon. 2020. “The Tumor Microenvironment.” Current Biology 30: R921–R925. 2. 1. Ashrafizadeh, M., S. Mirzaei, M. H. Gholami, et al. 2021. “Hyaluronic Acid‐based Nanoplatforms for Doxorubicin: a Review of Stimuli‐responsive Carriers, co‐delivery and Resistance Suppression.” Carbohydrate Polymers 272: 118491. 3. 1. Au, K. M., S. I. Park, and A. Z. Wang. 2020. “Trispecific Natural Killer Cell Nanoengagers for Targeted Chemoimmunotherapy.” Science Advances 6: eaba8564. 4. 1. Baghban, R., L. Roshangar, R. Jahanban‐Esfahlan, et al. 2020. “Tumor Microenvironment Complexity and Therapeutic Implications at a Glance.” Cell Communication and Signaling 18: 59. 5. 1. Basak, D., S. Arrighi, Y. Darwiche, and S. Deb. 2021. “Comparison of Anticancer Drug Toxicities: Paradigm Shift in Adverse Effect Profile.” Life (Basel) 12: 48. Show all 55 references ## MeSH terms * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Breast Neoplasms* / immunology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Breast+Neoplasms%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Breast+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Breast Neoplasms* / therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Breast+Neoplasms%2Ftherapy%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Breast+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Cell Line, Tumor Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cell+Line%2C+Tumor%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Cell+Line%2C+Tumor) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Extracellular Vesicles* / immunology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Extracellular+Vesicles%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Extracellular+Vesicles) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Extracellular Vesicles* / metabolism Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Extracellular+Vesicles%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Extracellular+Vesicles) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Female Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Female%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Female) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Humans Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Humans) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Hyaluronic Acid Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Hyaluronic+Acid%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Hyaluronic+Acid) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Immunotherapy* / methods Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Immunotherapy%2Fmethods%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Immunotherapy) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42814771/) * Killer Cells, Natural* / immunology Actions * [ Search in PubMed ](https://pubme
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