Antibody Generation Using Cancer‐Derived Small Extracellular Vesicles (sEVs): A Platform for Targeted Cancer Therapy and Potential Personalized Applications

Abstract Despite advances in tumor‐targeting therapies, drug delivery efficiency to solid tumors remains low in most preclinical studies, highlighting the need for more effective targeting ligands. A novel method is developed to generate tumor‐targeting monoclonal antibodies (mAbs) using cancer‐derived small extracellular vesicles (sEVs), which inherit the structural and functional features of their parent cells. sEVs isolated from human ovarian carcinoma cell lines (OVCAR‐8) are injected into mice to elicit an immune response. Hybridoma technology is used to generate mAbs, which are screened for either high specificity or cytotoxicity toward OVCAR‐8 cells. Two lead mAbs are individually decorated onto paclitaxel‐loaded CD8⁺ T cell‐derived sEVs (antibody‐functionalized TSEV/P; AB‐TSEV/P), and the resulting formulations are evaluated in OVCAR‐8 tumor‐bearing mice. Both AB‐TSEV/P formulations significantly reduce tumor growth without affecting body weight. Biodistribution studies using IR780‐loaded AB‐TSEV reveal enhanced tumor accumulation compared to non‐targeted controls. RNA sequencing and spatial transcriptomics show that antibody‐decorated sEVs induce transcriptional changes associated with immune activation and tumor suppression. This antibody generation strategy enables cancer cell‐specific targeting and supports its application in targeted cancer therapy and personalized oncology.