Strategies, Challenges and Application Prospects for Exosome Engineering Modifications in Tumor Targeted Therapeutics.

Nanodrugs have significantly revolutionized tumor therapy. Nevertheless, conventional nanodrug delivery systems suffer from a critical limitation: only ~0.7% of administered nanoparticles effectively accumulate in solid tumors, severely restricting clinical therapeutic efficacy. In recent years, exosomes-natural extracellular vesicles-have emerged as highly promising candidates for tumor-targeted drug delivery. Endowed with inherent low immunogenicity, excellent biocompatibility, and intrinsic capacity to traverse biological barriers, exosomes offer distinct advantages over conventional nanocarriers. Their characteristic lipid bilayer membrane not only protects encapsulated cargo but also enables surface engineering for functional optimization. Through strategic engineering modifications, exosomes can be endowed with enhanced tumor-targeting specificity, tunable payload release profiles, and multimodal functionalities, thus enabling the development of "smart" therapeutic platforms. This review systematically outlines current methodologies for exosome isolation and characterization, with a particular focus on engineering strategies aimed at augmenting tumor targeting. We comprehensively analyze approaches based on physical manipulation, chemical conjugation, and biological engineering. Furthermore, we summarize recent advances in exosome-based targeted cancer therapies and discuss key challenges related to scalability, standardization, regulatory approval, and clinical translation. Finally, we highlight emerging opportunities and future perspectives for next-generation exosome-engineered therapeutic development, aiming to provide a robust technical and conceptual foundation for advancing tumor therapy.