A biomimetic gas-protein co-delivery nanoplatform targets mitochondrial stress and GSDME activation for glioblastoma immunotherapy

Abstract

Glioblastoma (GBM) remains one of the most aggressive primary brain malignancies, with the therapeutic efficacy of conventional treatments and cancer immunotherapy being severely hindered by the blood-brain barrier (BBB) and the highly immunosuppressive tumor microenvironment (TME). Although pyroptosis, an inflammatory form of programmed cell death, can elicit potent antitumor immunity through the release of damage-associated molecular patterns (DAMPs), the precise induction of pyroptosis and the amplification of its immunostimulatory effects remain major challenges. Herein, we developed a biomimetic microglial cell membrane-coated nanosystem (M@GM) that integrates brain-targeted delivery, mitochondria-mediated damage, and innate immune activation for cascade-enhanced glioblastoma therapy. The nanosystem consists of a manganese carbonyl (MnCO) core loaded with Gasdermin E (GSDME) and cloaked with a microglial cell membrane, enabling efficient BBB penetration and active GBM targeting. Upon accumulation within the tumor microenvironment, M@GM responsively releases CO, Mn2+, and GSDME. CO and Mn2+ induced mitochondrial stress and ROS accumulation, which were accompanied by activation of the Caspase-3/GSDME axis and pyroptosis-associated cell death. The associated HMGB1 release and CRT exposure are consistent with an immunogenic cell death (ICD)-related response, while Mn2+ cooperatively activates the cGAS-STING innate immune pathway, promoting dendritic cell maturation, effector T-cell infiltration, and M1 polarization of tumor-associated macrophages, ultimately converting the immunologically “cold” GBM microenvironment into an immune-active “hot” phenotype. Both in vitro and in vivo studies demonstrated enhanced BBB transport and brain accumulation of M@GM, significantly inhibited GBM progression, prolonged the survival of tumor-bearing mice, and exhibited favorable biosafety. This work presents a biomimetic therapeutic strategy based on “biomimetic delivery-pyroptosis amplification-immune remodeling”, providing a promising design paradigm for brain-targeted nanomedicine-enabled cancer immunotherapy.