HER2-positive breast cancer brain metastasis (HER2+ BCBM) is a refractory malignancy with a high recurrence rate and poor prognosis. The efficacies of conventional treatments, including radiation and the FDA-approved drug trastuzumab, are compromised due to their significant obstacles, such as limited penetration through the blood-brain barrier (BBB), off-target effects on HER2+ tumor cells, and systemic adverse reactions, ultimately resulting in suboptimal therapeutic outcomes. In order to address these challenges, a novel biomimetic nanoplatform was created, which consisted of a combination of chimeric antigen receptor-natural killer (CAR-NK) cell-derived exosomes (ExoCAR), and a nanobomb (referred to as Micelle). This nanoplatform, known as ExoCAR/T7@Micelle, was designed to enhance the effectiveness of antitumor treatment by disrupting ferroptosis defense mechanisms. Due to the transferrin receptor binding peptide (T7) modification and CAR expression on the exosome surface, the nanoplatform successfully traversed the blood-brain barrier and selectively targeted HER2+ breast cancer cells. Moreover, integration of the reactive oxygen species (ROS) -amplified and photodynamic therapy (PDT)-based nanobomb facilitated the spatiotemporal release of the cargos at specific sites. Upon systemic administration of ExoCAR/T7@Micelle, mice with orthotopic HER2+ BCBM demonstrated a robust antitumor response in vivo, leading to a significant extension in survival time. Furthermore, histological analyses and blood index studies revealed no discernible side effects. Collectively, this study is the first to indicate the possibility of HER2+ BCBM therapy with a CAR-NK cell-derived biomimetic drug delivery system.Copyright © 2023 Elsevier B.V. All rights reserved.