Targeted delivery of hydrophobic drugs in vivo remains a significant challenge in cancer therapy. Extracellular vesicles (EVs), particularly those derived from leukocytes, offer an alternative strategy due to their natural tumor-targeting capabilities. However, EVs face difficulties in effectively and stably loading hydrophobic drugs. To address this challenge, we engineer a leukocyte-derived endogenous virus-like vesicle (VLV) system, built upon the activity-regulated cytoskeletal-associated (Arc) protein. Small molecule inhibitors targeting glutaminase (GLS) have shown promise in the treatment of triple-negative breast cancer (TNBC) but face limitations in vivo due to poor water solubility and challenges in targeted delivery into tumors. In this study, we combined natural tumor-targeting ability of leukocyte EVs and the robust encapsulation of hydrophobic small molecules by Arc capsids. Fully derived from native components in the human body, these engineered carriers effectively encapsulated and delivered GLS inhibitors into TNBC tumors. Our results demonstrate a substantial reduction in tumor growth and enhancement in survival rate, paving the way for targeted delivery of hydrophobic drugs into the inflammatory microenvironments of various pathological conditions.