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

Guanming Jiang,1,* Xuyi Liu,2,3,* Dou Zhang,2,3,* Zhenying Diao,2,3 Xiaojun Yang,1 Qinquan Tan,1 Shiyuan Chen,1 Wan Zhang,1 Xiumao Yin,1 Ting Yin,2,3 Xiaozhen Wang,4 Jianping Zhou5 1Department of Oncology, Tenth Affiliated Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, Guangdong, 523059, People’s Republic of China; 2Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong, 523808, People’s Republic of China; 3Dongguan Biomedical Nano Engineering Technology Research Center, Guangdong Medical University, Dongguan, Guangdong, 523808, People’s Republic of China; 4Respiratory department, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China; 5Department of Thoracic Surgery, Tenth Affiliated Hospital, Southern Medical University (Dongguan People’s hospital), Dongguan, Guangdong, 523059, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaozhen Wang, Respiratory Department, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China, Email [email protected] Jianping Zhou, Department of Thoracic Surgery, Tenth Affiliated Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, Guangdong, 523059, People’s Republic of China, Email [email protected]: 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.Keywords: non–small cell lung cancer, osimertinib resistance, hypoxia-inducible factor, vascular endothelial growth factor, epidermal growth factor receptor