Work

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

Year: 2026

Type: article

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, Mn 2+ , and GSDME. CO and Mn 2+ 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 Mn 2+ 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.

Source: Materials Today Bio

DOI: 10.1016/j.mtbio.2026.103750