Abstract The blood–brain barrier (BBB) severely blocks the intracranial accumulation of most systemic drugs. Inspired by the contribution of the bacterial outer membrane to Escherichia coli K1 (EC‐K1) binding to and invasion of BBB endothelial cells in bacterial meningitis, utilization of the BBB invasion ability of the EC‐K1 outer membrane for brain‐targeted drug delivery and construction of a biomimetic self‐assembled nanoparticle with a surface featuring a lipopolysaccharide‐free EC‐K1 outer membrane are proposed. BBB penetration of biomimetic nanoparticles is demonstrated to occur through the transcellular vesicle transport pathway, which is at least partially dependent on internalization, endosomal escape, and transcytosis mediated by the interactions between outer membrane protein A and gp96 on BBB endothelial cells. This biomimetic nanoengineering strategy endows the loaded drugs with prolonged circulation, intracranial interstitial distribution, and extremely high biocompatibility. Based on the critical roles of gp96 in cancer biology, this strategy reveals enormous potential for delivering therapeutics to treat gp96‐overexpressing intracranial malignancies.
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