Bionic Power Play: Dual-Targeting MDMX/MDM2 to Reboot p53 to Beat Lung Adenocarcinoma’s Immune Tricks

Solomon Wong,1,* Lu Xu,2,* Weiming You,3,4 Wangxiao He,4 Xiaoqiang Zheng,4,5 Zhongquan Qi1,6 1School of Medicine, Guangxi University, Nanning, 530004, People’s Republic of China; 2Department of Physiology, Xiamen Medical College, Xiamen, 361023, People’s Republic of China; 3Department of Hepatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China; 4Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China; 5Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China; 6Fujian Provincial Sperm Bank, Fujian Maternity and Child Health Hospital, Fuzhou, 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoqiang Zheng, Email [email protected] Zhongquan Qi, Email [email protected] and Aim: MDM2 and MDMX are key regulators of the tumor suppressor p53 and are implicated in immune escape mechanisms in lung adenocarcinoma. Overexpression of these proteins inhibits p53 activity, limiting the immune system’s ability to recognize and clear tumor cells, contributing to resistance against immune checkpoint inhibitors (ICIs). This study introduces a novel bionic peptide nanodrug, E@MDP, designed to target both MDM2 and MDMX, reactivate p53, and enhance the effectiveness of PD-1 immune checkpoint therapy in lung cancer.Methods: E@MDP is constructed using a gold-mediated self-assembly method to form peptide-loaded nanoparticles, which are then encapsulated in erythrocyte membranes, enhancing stability and cell penetration. The physicochemical properties of the bionic nanodrug were evaluated, and its therapeutic efficacy was validated in vitro in LLC cells and in vivo using a syngeneic subcutaneous lung adenocarcinoma mice model.Results: In vitro, E@MDP reinstated functional p53 activity, demonstrating a 2.46-fold upregulation compared to control groups, and significantly promoted tumor cell apoptosis, exhibiting a 3.9-fold enhancement. In vivo, E@MDP potentiated PD-1 checkpoint blockade by reprogramming the tumor immune microenvironment, ultimately driving a nearly two-fold enhancement in tumor regression versus monotherapies. Importantly, the E@MDP nanodrug exhibited favorable safety profiles, with no significant toxicity observed in preclinical models.Conclusion: The E@MDP is a promising strategy for lung cancer immunotherapy and overcomes several limitations of conventional peptide drugs. The bionic nanodrug platform holds great potential for broader applications in cancers characterized by immune evasion.Keywords: lung adenocarcinoma, immunotherapy, MDM2/MDMX, peptide, nanomedicine