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Traditional tumour treatment methods such as radiotherapy and chemotherapy can lead to the accumulation of senescent cells in tumours. Treatment\u2010induced senescence (TIS) can lead to incomplete tumour clearance and potential recurrence. Recently, the combination of chemotherapy drugs and senolytics drugs (\u2018one\u2010two punch\u2019 therapy) has become a promising strategy for improved tumour treatment, but this method also faces challenges in terms of safety and targeting specificity. In order to further improve the efficacy of chemotherapy on OS, here we developed a senolytic drug delivery system based on engineered Natural killer (NK) cell\u2010derived extracellular vesicles (EVs) that can target OS cells. EVs were engineered to contain doxorubicin (Dox), termed iRGD\u2010EVs\u2010Dox, and used to induce cellular senescence in OS cells, followed by delivery of the Bcl\u20102 family inhibitor ABT\u2010263 in similar engineered EVs (iRGD\u2010EVs\u2010ABT\u2010263), to specifically eliminate the senescent OS cells induced by Dox. Our results demonstrate that iRGD\u2010EVs have efficient targeting ability to OS cells and iRGD\u2010EVs\u2010ABT\u2010263 effectively induced senolysis of Dox\u2010induced senescent OS cells in vitro and repressed tumour growth in OS cell xenograft mouse models. Taken together, our results demonstrate the therapeutic efficiency of using engineered EVs from NK cells to deliver first a chemotherapeutic agent to induce senescent OS cells followed by a senolytic drug to eliminate chemotherapy\u2010induced senescent OS cells, providing a novel strategy for more effective cancer treatment.<\/jats:p>","DOI":"10.1002\/jev2.70123","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T11:10:02Z","timestamp":1753182602000},"source":"Crossref","is-referenced-by-count":19,"title":["NK\u2010Cell\u2010Derived Extracellular Vesicles Engineered to Carry Senolytics Eliminate Chemotherapy\u2010Induced Senescent Osteosarcoma Cells"],"prefix":"10.1002","volume":"14","author":[{"given":"Xianlin","family":"Yue","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems Shandong First Medical University &amp; Shandong Academy of Medical Sciences  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