Tabriz University of Medical Sciences BioImpacts 2228-5652 16 1 2026 01 04 Targeted delivery of doxorubicin using RSV F-protein modified breast cancer-derived exosomes in breast cancer-bearing mice 33180 33180 10.34172/bi.33180 EN Narges Mardi https://orcid.org/0000-0002-3747-2816 Amir Zarebkohan Cigir Biray-Avci Reza Rahbarghazi Mehdi Talebi Hamid Lotfimehr Sharareh Khavandkari Zahra Abbasi-Malati Nastaran Sedghi-Samarkhazan Elham Shahriyari Asghar Khalilnezhad Morteza Milani https://orcid.org/0000-0002-9822-703X Mohammad Nouri https://orcid.org/0000-0002-5367-9956 Journal Article 10.34172/bi.33180 2025 11 22 2026 01 25 Introduction: Triple-negative breast cancer demonstrated high metastasis and mortality rates in female populations. Emerging data on effective targeting and specific internalization of chemotherapeutic agents, using modified exosomes, decreased the therapeutic dosage of anti-cancer drugs in cancer cells. Methods: Herein, we developed modified exosomes by surface decoration using the Fusion protein of Respiratory Syncytial Virus (F-protein of RSV) through Click-chemistry techniques, and Dox-loaded via sonication strategy. Then, the viability and metastatic behaviors of MDA-MB-231 cells were monitored in the presence of different groups, including Dox, Exosomes (Exo), Exosomes loaded with Dox (Exo@Dox), and F-protein coupled Exosome groups (Exo-F) and (Exo-F@Dox). Results: In vitro and in vivo results verified that the F-protein coupled exosome, as a modified natural nanoplatform, possessed a biocompatible nature in blood circulation and crossing of blood barriers. After exposure to tumoral temperature (40 °C) and lysosomal PH (5.5) demonstrate amplified Dox release (around 60% at 8 h). Also, in vitro uptake results confirmed a significant increase in Exo-F internalization compared to the Exo group in MDA-MB-231 cells (P<0.0001). Correspondingly, the IC50 value of Exo-F@Dox versus free Dox showed a significant reduction (24-fold more potent) (P<0.0001). Interestingly, Dox-free modified Exo (Exo-F) showed appreciable cytotoxicity (IC50 of about 0.1 µg /mL for exosomal protein concentration) (P˂0.0001). Also, migration assay results confirmed a considerable decrease in the migrated population of MDA-MB-231 cells (10%) compared to the control group, following exposure to modified exosomes. Interestingly, an in vivo study in tumor-bearing Balb/c mice demonstrated a significantly decreased tumor size in the Exo-F groups compared to other formulations. Conclusion: In summary, F-protein modified exosomes exhibited superior anticancer efficacy by improving tumor-specific targeting, ensuring precise delivery of chemotherapeutic agents, facilitating efficient drug release, and allowing for lower therapeutic dosages.