A Hybrid Protein-Oxygen Nanomedicine Overcomes Osimertinib Resistance in NSCLC via HIF-1α/VEGF/EGFR Inhibition.

Purpose: Osimertinib, established as the frontline treatment for advanced non-small cell lung cancer (NSCLC), can effectively prolong progression-free survival. However, it faces the problem of reduced treatment persistence due to acquired drug resistance. Meanwhile, tumor hypoxia is also a key driver of drug resistance. This study proposes a hybrid protein oxygen nanocarrier combined with osimertinib and ginsenoside Rg3 to address the drug resistance issue of NSCLC through multiple mechanisms. Methods: A hybrid protein-oxygen multifunctional nanoplatform (OG@HPO) was engineered by co-encapsulating OSI and GRg3 within oxygen-rich protein matrices. Initial confirmed the synthesis of OG@HPO and characterized its drug/oxygen release. Subsequent in vitro assays verified OG@HPO's tumoricidal activity and elucidated its mechanistic. Finally, in vivo evaluations validated the nanoplatform's tumor targeting and anticancer efficacy. Results: Preliminary experiments confirmed successful OG@HPO preparation and validated its drug/oxygen release capacities. In vitro assays demonstrated the potent cytotoxic effects of OG@HPO against H1975 OR cells. In vivo biodistribution studies revealed excellent tumor-targeting of OG@HPO in H1975 OR xenograft mice. Subsequent 18 days therapeutic monitoring showed superior antitumor efficacy accompanied and favorable biosafety profile of OG@HPO. More importantly, in vitro and in vivo studies demonstrated that OG@HPO effectively oxygenate tumor microenvironment, thereby inhibiting hypoxia-driven HIF-1α expression and simultaneously inhibiting the vascular endothelial growth factor (VEGF)/EGFR pathway. Conclusion: OG@HPO represents an innovative multifunctional nanoplatform integrating tumor-targeting, multi-drug delivery, and hypoxia modulation capabilities. By effectively alleviating tumor hypoxia, it achieves multiple inhibition of HIF-1α and EGFR/VEGF pathways. Ultimately, enhances NSCLC sensitivity to osimertinib, thereby reversing acquired resistance. Overall, OG@HPO is regarded as a promising strategy to overcome osimertinib resistance providing a clinically translatable solution.