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

Sep 23, 2026

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MDM2 and MDMX regulate the tumor suppressor p53 and participate in immune escape mechanisms in lung adenocarcinoma. This study presents a bionic peptide nanodrug, E@MDP, engineered to target both MDM2 and MDMX, reactivate p53, and improve PD-1 immune checkpoint therapy. Gold-mediated self-assembly forms peptide-loaded nanoparticles, encapsulated in erythrocyte membranes. E@MDP restores functional p53, enhances apoptosis in LLC cells, and reprograms the tumor immune microenvironment in syngeneic mice, improving regression versus monotherapies with favorable safety.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

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Background and Aim

Methods

Results

Conclusion

Introduction

International Journal of Nanomedicine Open Access Full Text Article ORIGINAL RESEARCH Bionic Power Play: Dual-Targeting MDMX/MDM2 to Reboot p53 to Beat Lung Adenocarcinoma’s Immune Tricks Solomon Wong 1 , *, Lu Xu2 , *, Weiming You 3 ,4 , Wangxiao He4 , Xiaoqiang Zheng 4 , 5 , Zhongquan Qi 1 , 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 work Correspondence: Xiaoqiang Zheng; Zhongquan Qi, Email [zhengxiaoqiang@xjtu.edu.cn](zhengxiaoqiang@xjtu.edu.cn); [yxyyz@gxu.edu.cn](yxyyz@gxu.edu.cn) | Background 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 | | --- | | Introduction
MDM2 and MDMX are key regulators of p53, 1 often engaged in immune escape mechanisms in a number of cancers, such as lung adenocarcinoma.2,3 MDM2 and MDMX have been shown to suppress p53 activity, thereby limiting the immune system from effectively recognizing and clearing tumor cells.4,5 Specifically, in wild-type p53 lung adenocarcinomas, MDM2/MDMX overexpression promotes immune escape, thereby conferring resistance to immune checkpoint inhibitors like ICIs.6–8 Mechanistically, MDM2/MDMX upregulation suppresses p53-dependent pathways involved in antigen presentation, interferon signaling, and the expression of key chemokines, thereby impairing major histocompatibility complex class I expression and reducing T cell infiltration and activation within the tumor.9, 10 This results in | Received: 8 April 2025 Accepted: 4 August 2025 Published: 13 August 2025 Internat

FAQs

What problem do MDM2 and MDMX contribute to in lung adenocarcinoma?

MDM2 and MDMX suppress p53 activity, which enables immune escape in lung adenocarcinoma and contributes to resistance to immune checkpoint inhibitors.

How is the E@MDP bionic nanodrug designed?

E@MDP is built using gold-mediated self-assembly to create peptide-loaded nanoparticles, which are then encapsulated in erythrocyte membranes to enhance stability and cell penetration.

What therapeutic effects does E@MDP show in vitro and in vivo?

In vitro, E@MDP reinstates functional p53 activity and promotes tumor cell apoptosis. In vivo, it enhances PD-1 checkpoint blockade by reprogramming the tumor immune microenvironment and drives stronger tumor regression versus monotherapies.

Sep 23, 2026

Uploaded by Dipper