Recently, Professor Ding Ya's team from the School of Pharmacy at our university published their latest research findings in the prestigious journal Advanced Materials. The study, titled “Artificial Transmembrane Oligopeptide-Integrated Interferon mRNA with Monoclonal Antibody to Improve Specificity and Efficacy of Cancer Immunotherapy,” was released online. Yan Yinyu, a 2021 doctoral candidate at our university, is the first author of the paper. Professor Ding Ya from the School of Pharmacy is the sole corresponding author, with China Pharmaceutical University listed as the sole corresponding institution.
Tumor immunotherapy activates or enhances systemic immune responses to specifically recognize and eliminate tumor cells, a complex process involving multiple stages and steps. Consequently, monotherapy struggles to effectively regulate the entire immune cycle, while combination immunotherapies, though synergistic, often carry additive toxicity. Interferon beta (IFNβ) demonstrates unique advantages in tumor immunotherapy due to its ability to modulate immune responses across multiple dimensions, including recognition, effector functions, and memory. However, traditional systemic administration often induces systemic toxicity and tumor PD-L1 upregulation, limiting its clinical utility.
To enhance combined immunotherapy efficacy while minimizing adverse effects, this study developed a novel, simple, and universal artificial transmembrane oligopeptide platform: cholesterol-modified polylysine (CPL) serves as a linker to integrate IFNβ mRNA with anti-PD-L1 monoclonal antibody (aPD-L1) into complex particles (aCmRi). Its core advantage lies in CPL's ability to deliver mRNA directly into the cytoplasm via membrane interactions, bypassing the classical lysosomal pathway and enhancing mRNA transfection efficiency. Concurrently, CPL increases lysosomal permeability in tumor cells, promoting apoptosis and upregulating MHC I expression. Surface-anchored aPD-L1 bridges the distance between particles and tumor cells while blocking PD-L1 on tumor cell surfaces, synergizing with in situ expressed IFNβ. This work offers a solution to address IFNβ's non-specific targeting and in vivo toxicity, providing a simple and universal mRNA therapeutic approach to enhance the efficacy, selectivity, and safety of tumor immunotherapy in vivo.
This research was supported by the National Natural Science Foundation of China, the Jiangsu Provincial Key R&D Program of Science and Technology Special Funds, and the “Double First-Class” Initiative funding from China Pharmaceutical University.
Original article link: https://doi.org/10.1002/adma.202503139
Schematic Diagram of the Mechanism of Tumor Immunotherapy Mediated by Artificial Transmembrane Oligopeptides Targeting Cytokine mRNAs
