Biomimetic arsenic trioxide nanoplatform induces Caspase-3/GSDME pyroptosis and remodels the glioma immune microenvironment

Abstract

Glioma (GBM) is characterized by severe invasiveness and grim clinical outcomes. The therapeutic efficacy of conventional treatments is severely constrained by the blood-brain barrier (BBB), while the immunosuppressive tumor microenvironment (TME) further compromises treatment responsiveness. In GBM, abnormal expression of pyroptosis-related genes is closely associated with tumor malignancy and patient prognosis. Core pyroptosis-related genes were identified through bioinformatics screening. The active component arsenic trioxide (ATO) from traditional Chinese medicine was employed as a therapeutic agent, and it possesses unique advantages in inducing pyroptosis in tumor cells. Herein, we developed a brain-targeted biomimetic nanoplatform, termed As/ZIF-8@CM-RVG29. The engineered nanoplatform exhibited efficient BBB penetration, enhanced tumor accumulation, and pH-responsive drug release. ATO triggered Caspase-3/GSDME-dependent pyroptotic cell death in glioma cells, remodeled the tumor immune microenvironment, and effectively suppressed orthotopic glioma growth. Furthermore, combination treatment with programmed cell death protein-1 (αPD-1) generated a synergistic antitumor response and significantly prolonged median survival in tumor-bearing mice. Collectively, these findings suggest a promising therapeutic strategy and provide evidence for the development of targeted immunotherapy against glioma.