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

Abstract 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.