Abstract

The third-generation of EGFR-TKI osimertinib has been approved as a first-line therapy in NSCLC , representing the most successful advance in molecularly targeted therapy. However, the rapid development of osimertinib resistance renders the unsustainable treatment benefit. Plus, brain metastasis (BMs) is a major mortality cause for NSCLC; there is no drug specifically approved for the osimertinib-resistant BMs of NSCLC yet. To tackle these critical issues, a BBB-permeable biomimetic codelivery system was designed for specifically treating osimertinib-resistant BMs. The T12 peptide-modified albumin nanoparticles coloaded with regorafenib and disulfiram/copper ion chelate repolarized the tumor-promoting CD206 hi TGF-β1 + MΦ via inhibition of FROUNT and thus remodeled tumor immune microenvironment. The treatment efficacy in both the subcutaneous H1975/AZDR model and the brain metastasized model demonstrated the effectiveness of the BBB-penetrating combination therapy and the macrophage-mediated innate immunity. This nanotherapeutic combination strategy provides a translational solution to the formidable challenges of overcoming TKI resistance and treating the TKI-resistant BMs.