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 generated 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.