Multieffect Specific Nanovesicles for Homing Resistant Tumors and Overcoming Osimertinib‐Acquired Resistance in NSCLC

Acquired resistance to osimertinib (Osi) remains a major obstacle in the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). AXL elevation is a known key mechanism of Osi-resistance, and therapeutic strategies remain scarce. Emerging evidence reveals that an increased intracellular glutathione (GSH) level induces Osi resistance. In this study, a new mechanism is identified by which GSH regulates AXL expression via glutathione peroxidase 4 (GPX4) in Osi-resistant cells. A multifunctional covalent organic framework (COF) nanoplatform for GSH consumption, AXL inhibition, and co-delivery of the AXL inhibitor (Brigatinib) and Osi is creatively constructed to confirm whether Osi sensitivity improves by simultaneously targeting GSH-AXL resistance mechanisms. Furthermore, it is coated, for the first time, the COF carrier system with specific vesicles to precisely home it into resistant tumors, where CDH2 adhesion molecules play a crucial role. The engineered multifunctional antiresistance-specific nanovesicles effectively inhibited the GSH-AXL axis, induced apoptosis in Osi-resistant cells both in vitro and in vivo, and delayed the progression of Osi-resistant tumors. Overall, these findings provide a novel strategy to overcome the Osi-acquired resistance caused by high AXL levels in NSCLC.