A biomimetic gas-protein co-delivery nanoplatform targets mitochondrial stress and GSDME activation for glioblastoma immunotherapy.
6 affiliations
- 1Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
- 2Department of Thyroid and Breast Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China.
- 3School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
- 4Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, The Second People's Hospital of Huai'an, Huai'an, 223002, China.
- 5The Affiliated Pizhou Hospital of Xuzhou Medical University, Jiangsu, 221399, China.
- 6Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, China.
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.
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BibTeX
@article{ma2026biomimetic,
title = {{A biomimetic gas-protein co-delivery nanoplatform targets mitochondrial stress and GSDME activation for glioblastoma immunotherapy.}},
author = {Guangyu Ma and Junjie Li and Kai Wang and Dehong Yu and Jiale Li and Ming Guan and Fenglei Gao and Zhao Liu and Jun Lan},
journal = {Materials today. Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103750},
url = {https://europepmc.org/article/MED/42926787},
note = {CC BY},
}
RIS
TY - JOUR
TI - A biomimetic gas-protein co-delivery nanoplatform targets mitochondrial stress and GSDME activation for glioblastoma immunotherapy.
AU - Guangyu Ma
AU - Junjie Li
AU - Kai Wang
AU - Dehong Yu
AU - Jiale Li
AU - Ming Guan
AU - Fenglei Gao
AU - Zhao Liu
AU - Jun Lan
PY - 2026
DA - 2026/10/12
JO - Materials today. Bio
DO - 10.1016/j.mtbio.2026.103750
UR - https://europepmc.org/article/MED/42926787
AB - 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.
SN - 2590-0064
ER -