Engineered Macrophage Exosome-Mediated Delivery of IL-2-mRNA for Glioblastoma Treatment

GBM (glioblastoma multiforme) is a common primary malignant tumor of the central nervous system, whose treatment efficacy is severely limited by the dual barriers of the blood-brain barrier and the immu nosuppressive tumor microenvironment. IL-2 (interleukin-2), as a potent immunotherapeutic agent, demonstrates significant anti-tumor effects; however, its clinical application is greatly restricted by severe side effects associated with high systemic doses. To address these challenges, this study developed a novel gene delivery system, termed cExo@LmNPs, which consists of IL-2 mRNA-loaded LNPs (lipid nanoparticles) encapsulated within exosomes de rived from M1 macrophages overexpressing CD161. The physicochemical properties of cExo@LmNPs were characterized using nanoparticle tracking analysis, agarose gel electrophoresis, Western blot, and cellular fluorescence imaging. In vitro studies using mouse primary T cells demonstrated that cExo@LmNPs significantly enhanced IL-2 expression, promoted T cell proliferation, and enhanced the specific cytotoxicity against GL261 tumor cells. In an orthotopic GBM mouse model, cExo@LmNPs exhibited superior tumor-targeting capability compared with plain LNPs. Furthermore, cExo@LmNPs treatment markedly promoted the proliferation and activation of CD4⁺ T and CD8⁺ T cells, increased M1 macrophage polarization, and resulted in significant tumor suppression with control lable systemic toxicity and good biosafety. In conclusion, cExo@LmNPs represent a promising strategy for the safe and efficient delivery of IL-2-mRNA across the blood-brain barrier to tumor sites, effectively reshaping the im munosuppressive microenvironment and enhancing anti-tumor immunity, thereby offering a novel therapeutic ap proach for GBM treatment.

CSTR: 32200.14.cjcb.2026.03.0018