Hybrid nanovesicles enhance antitumor efficacy in KRAS-mutant non-small cell lung cancer.

KRAS mutations are key drivers of NSCLC, but effective targeted therapies remain scarce due to frequent resistance. EGFR phosphorylation has emerged as a central mechanism underlying acquired resistance to KRAS inhibitors. To overcome this, we developed a hybrid nanovesicle (hNV)-mediated combination therapy based on a membrane-mimetic hNV platform embedded with EGFR-targeted nanobodies (EGa1), termed EGa1-hNVs, which display high-affinity EGFR-targeting ligands and enable the co-delivery of KRAS inhibitors. We evaluated this nanocarrier-based therapeutic strategy for delivering the KRASG12D inhibitor MRTX1133 in KRASG12D-mutant cell lines and animal models. In vitro, EGa1-hNVs@MRTX1133 (EGa1-hNVs-M) blocked pAKT/pERK signaling and inhibited MRTX1133-mediated EGFR activation. Given that EGa1-hNVs-M treatment still upregulated PD-L1 expression, we further combined it with an anti-PD-L1 antibody (αPD-L1) treatment. This combined strategy (EGa1-hNVs-MP) elicited a potent systemic antitumor response in KRASG12D-mutant NSCLC models. Mechanistically, it reprograms the tumor microenvironment by sustaining MAPK and PI3K pathway inhibition, reducing EGFR phosphorylation, enhancing CD8+ T-cell infiltration, and restoring antitumor immunity through PD-L1 blockade. By exploiting the signaling vulnerabilities of KRAS-driven tumors, our hybrid nanovesicle platform provides a promising therapeutic strategy for overcoming resistance and improving therapeutic response in KRAS-mutant NSCLC.