DH5α Outer Membrane‐Coated Biomimetic Nanocapsules Deliver Drugs to Brain Metastases but not Normal Brain Cells via Targeting GRP94

Receptor‐mediated vesicular transport has been extensively developed to penetrate the blood‐brain barrier (BBB) and has emerged as a class of powerful brain‐targeting delivery technologies. However, commonly used BBB receptors such as transferrin receptor and low‐density lipoprotein receptor‐related protein 1, are also expressed in normal brain parenchymal cells and can cause drug distribution in normal brain tissues and subsequent neuroinflammation and cognitive impairment. Here, the endoplasmic reticulum residing protein GRP94 is found upregulated and relocated to the cell membrane of both BBB endothelial cells and brain metastatic breast cancer cells (BMBCCs) by preclinical and clinical investigations. Inspired by that Escherichia coli penetrates the BBB via the binding of its outer membrane proteins with GRP94, avirulent DH5α outer membrane protein‐coated nanocapsules (Omp@NCs) are developed to cross the BBB, avert normal brain cells, and target BMBCCs via recognizing GRP94. Embelin (EMB)‐loaded Omp@EMB specifically reduce neuroserpin in BMBCCs, which inhibits vascular cooption growth and induces apoptosis of BMBCCs by restoring plasmin. Omp@EMB plus anti‐angiogenic therapy prolongs the survival of mice with brain metastases. This platform holds the translational potential to maximize therapeutic effects on GRP94‐positive brain diseases. GRP94‐targeting biomimetic nanocapsules are constructed by surface coating of DH5α outer membrane proteins for specific drug delivery to brain metastases while sparing normal brain cells. Embelin‐loaded nanocapsules can specifically degrade neuroserpin in metastatic tumor cells to restore local generation of plasmin for L1CAM cleavage, which can suppress the vascular co‐option growth of brain metastases and reverse resistance to anti‐angiogenic therapy.