Artificial Transmembrane Oligopeptide‐Integrated Interferon mRNA with Monoclonal Antibody to Improve Specificity and Efficacy of Cancer Immunotherapy

Abstract Combination therapy to improve the immunotherapy response rate without causing treatment toxicity remains a significant challenge. Here, an artificial transmembrane oligopeptide, cholesterol‐grafted polylysine (CPL), is synthesized to integrate mRNA with a monoclonal antibody into a single system. CPL with a 6% substitution degree is optimized and complexed with IFNβ mRNA to form CmRi nanoparticles. Subsequently, anti‐PD‐L1 monoclonal antibody (aPD‐L1) is modified on the surface of CmRi to produce aCmRi nanoparticles. Notably, CPL facilitates cytosolic delivery via a membrane‐interacting mechanism, thereby bypassing lysosomal degradation of mRNA. RNA sequencing analysis revealed that CPL promoted tumor cell apoptosis and upregulated MHC I expression by disrupting lysosomes in tumor cells. Additionally, CPL combined tumor cell‐targeting and PD‐L1 inhibitory functions of aPD‐L1 with the multidimensional immunoadjuvant properties of in situ‐expressed IFNβ. This approach overcame the side effects of IFNβ while fully leveraging its therapeutic potential. In a B16‐F10 melanoma mouse model, aCmRi demonstrated a superior mRNA transfection rate (26.1%) and achieved the highest tumor suppression rate (89.9%) among all test formulations, without causing significant toxicity. This study presents a simple and versatile strategy to enhance the efficacy, selectivity, and safety of tumor immunotherapy in vivo.