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© 2021 American Chemical Society.Biomimetic cell membrane–coated nanoparticles have been broadly applied because of their superior biochemical properties. The right–side–out cell membrane coating manner provides nanoparticles with an immune–evasive stealth function in vivo. However, this acts as a drag for drug discovery when the drug targets are the intracellular domain of transmembrane receptors. Herein, inside–out–oriented cell membrane–coated nanoparticles were prepared for screening tyrosine kinase inhibitors, which specifically interacted with the intracellular kinase domain of the epidermal growth factor receptor. Biotinylated human lung adenocarcinoma epithelial cell membranes specifically interacted with streptavidin–immobilized Fe3O4 magnetic nanoparticles and then formed inside–out–oriented cell membrane–coated magnetic nanoparticles (IOCMMNPs). The cell membrane orientation of the IOCMMNPs was successfully confirmed by immunogold electron microscopy, fluorescently labeled confocal microscopy, sialic acid quantification assay, and the adsorption capacity assay. Moreover, IOCMMNPs possessed satisfactory binding capacity, selectivity, and high sensitivity (limit of detection = 0.4 × 10–3 μg mL–1). Ultimately, IOCMMNPs successfully targeted two main compounds from Strychnos nux–vomica whose potential antitumor activities were further validated by pharmacological studies. The application of the inside–out cell membrane coating strategy further enhances the drug screening efficiency and broadens the insight and methodologies for drug lead discovery. This inside–out cell membrane coating concept also provides a method for the future development of engineered cell membrane–coated nanotechnology.
