Engineering Extracellular Vesicles for Tumor Targeted Therapy: Source Optimization, Modification, and Clinical Application

Jiaxin Sui,1– 5,* HanBin Qin,2– 6,* Zile Zhang,2– 5,7 Xiaojing Lv,1– 5 Xinhua Lin,2– 6 Zhonglu Liu,2– 5 Xin Zhao,2– 5 Xuexia Liu,8 Hua Zhang2– 5 1Qingdao University Medical College, Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 2Department of Head and Neck Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, People’s Republic of China; 3Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, Shandong Province, People’s Republic of China; 4Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong Province, People’s Republic of China; 5Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong Province, People’s Republic of China; 6School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, People’s Republic of China; 7Second Clinical Medical College, Binzhou Medical University, Yantai, Shandong Province, People’s Republic of China; 8Shandong Stem Cell Engineering Technology Research Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuexia Liu, Email [email protected] Hua Zhang, Email [email protected]: Cancer remains a leading cause of global morbidity and mortality, yet conventional therapies, including surgery, radiotherapy, and chemotherapy, are often limited by invasiveness, systemic toxicity, and drug resistance. In this context, extracellular vesicles (EVs) have emerged as a promising cell-free nanotherapeutic platform. As endogenous nanocarriers, EVs enable precise, targeted delivery of diverse bioactive cargoes (eg, nucleic acids, chemotherapeutics, immunomodulators) to tumor tissues, thereby enhancing therapeutic efficacy while minimizing off-target effects, which is the key advantages for their application in tumor targeted therapy. This review systematically summarizes the characteristics of animal-derived and plant-derived EVs and highlights their translational applications in multiple cancers via immune activation, targeted delivery, tumor microenvironment remodeling, and anti-angiogenesis. We further introduce advanced bioengineering strategies for EV modification to optimize cargo loading, targeting specificity, and in vivo stability, particularly frontier innovations such as artificial intelligence-assisted design and microfluidic manufacturing that improve the precision, controllability, and scalability of engineered EVs. Compared to synthetic nanocarriers, EVs exhibit unique advantages, including excellent biocompatibility, low immunogenicity, and superior ability to cross biological barriers. However, the clinical application of EV-based therapies faces notable challenges, including EV heterogeneity, scalability of production, standardization of characterization methods, cargo loading efficiency, and long-term safety concerns. This review emphasizes the transformative potential of engineered EVs in advancing tumor targeted therapy and improving outcomes for patients with refractory or metastatic tumors. Keywords: extracellular vesicles, EVs, engineered EVs, tumor targeted therapy, tumor microenvironment, clinical translation