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Life sciences · Journal article
Cancer Nanotechnology · September 27, 2026
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Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes, with high metastatic potential, frequent recurrence, and limited treatment options due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Although tumor-suppressive microRNA (miRNA) replacement therapy offers a promising avenue for precision oncology, its therapeutic application is constrained by poor stability and the lack of efficient tumor-targeted delivery systems. Receptor targeting engineered small extracellular vesicles (sEVs) have emerged as attractive nanotechnology-based carriers because of their inherent biocompatibility, low immunogenicity, and ability to transport functional nucleic acids. However, the development of selective sEVs-mediated miRNA delivery platforms for epidermal growth factor receptor 1 (EGFR1)-overexpressing TNBC has not been fully explored. We developed an EGFR1-targeted sEVs platform by surface-functionalizing HEK293-derived sEVs with the EGFR1 targeting, GE11 peptide and loading them with the tumor-suppressive miRNA, miR-204. GE11-functionalized sEVs retained their physicochemical integrity following peptide conjugation and miRNA incorporation, and exhibited enhanced uptake in EGFR1-overexpressing TNBC cells compared with non-TNBC cells. Targeted delivery of miR-204 significantly inhibited TNBC cell proliferation, clonogenic growth, migration, and invasion in vitro. Quantitative proteomic profiling identified a distinct miR-204-associated molecular signature, revealing a subset of downregulated proteins implicated in tumor progression. Furthermore, therapeutic efficacy was validated in an ex vivo TNBC spheroid model, where GE11-engineered miR-204-loaded sEVs suppressed spheroid growth. Importantly, the engineered sEVs formulation demonstrated excellent biocompatibility without compromising vesicle stability. GE11-engineered sEVs provide an effective and selective nanocarrier platform for targeted delivery of miR-204 in EGFR1-positive TNBC. By combining receptor-mediated targeting with miRNA replacement therapy, this strategy enhances therapeutic specificity and anti-tumor efficacy, highlighting GE11-engineered sEVs as a promising targeted delivery platform that warrants further in vivo evaluation toward precision nanomedicine applications.