Surfaceome Reprogramming of Stemsomes Promotes Lung Cancer Targeting via Potentiated Receptor–Ligand Interactions

ABSTRACT Non‐small‐cell lung cancer (NSCLC) mortality remains high because mutation‐specific therapies target only small patient subsets and inevitably encounter drug resistance. In this regard, multipathway‐assisted mesenchymal stem cell‐derived nanovesicles (stemsomes) offer a promising universal platform for overcoming the unmet needs of lung cancer therapeutics, particularly for patients lacking identifiable oncogenic drivers. This study introduces a novel strategy in which dexamethasone, a compound conventionally used as an anti‐inflammatory drug, is repurposed to enhance the tumor‐targeting capabilities of stemsomes. Nanoparticles engineered by fusing these dexamethasone‐primed stemsomes with liposomes exhibit markedly improved therapeutic effects. According to transcriptomic and siRNA‐mediated knockdown experiments, this enhanced targeting of tumor cells is driven by the dexamethasone‐induced upregulation of key cell adhesion proteins, specifically ephrin type‐A receptor 2 and neurogenic locus notch homolog protein 3. Furthermore, a comprehensive map of potential adhesion interactions and computational simulations suggest a multivalent interaction network between the surfaces of dexamethasone‐primed stemsomes and NSCLC H1975 cells. These findings indicate the discovery of a highly translational and mutation‐independent strategy that represents a promising novel mechanism for engineering vesicle surfaces for NSCLC therapy.