Biomimetic membrane-coated nanoparticles specially permeate the inflammatory blood-brain barrier to deliver plasmin therapy for brain metastases.

Many brain-targeting drug delivery strategies have been reported to permeate the blood-brain barrier (BBB) via hijacking receptor-mediated transport. However, these receptor-based strategies could mediate whole-brain BBB crossing due to the wide intracranial expression of target receptors and lead to unwanted accumulation and side effects on healthy brain tissues. Inspired by brain metastatic processes and the selectivity of brain metastatic cancer cells for the inflammatory BBB, a biomimetic nanoparticle was developed by coating drug-loaded core with the inflammatory BBB-seeking erythrocyte-brain metastatic hybrid membrane, which can resist homotypic aggregation and specially bind and permeate the inflammatory BBB for specific drug delivery. Dexamethasone and embelin were used as model drugs to be loaded in the biomimetic nanoparticles to restore plasmin-mediated attacks against brain metastases. The drug-loaded nanoparticles were proved to inhibit tumor serpin secretion to restore local plasmin production, which could inactivate tumor cell surface L1CAM to inhibit vessel-spreading-dependent tumor growth and produce lethal soluble factor-related apoptosis ligands (sFasL) to induce tumor cell apoptosis, leading to the suppression of the intracranial metastatic nodule development and prolonged survival of mice with brain metastases. The inflammatory BBB-seeking biomimetic approach represents an effective regimen for potent therapy against brain metastases.