Enhanced pyroptosis induction with pore-forming gene delivery for osteosarcoma microenvironment reshaping

Jing-Jun Nie; Bowen Zhang; Peng Luo; Maoguo Luo; Yuwen Luo; Jingjing Cao; Honggang Wang; Jianping Mao; Yonggang Xing; Weifeng Liu; Yuning Cheng; Renxian Wang; Yajun Liu; Xinbao Wu; Xieyuan Jiang; Xiaoguang Cheng; Chi Zhang; Da-Fu Chen

Bioactive Materials (Aug 2024)

Enhanced pyroptosis induction with pore-forming gene delivery for osteosarcoma microenvironment reshaping

Jing-Jun Nie,
Bowen Zhang,
Peng Luo,
Maoguo Luo,
Yuwen Luo,
Jingjing Cao,
Honggang Wang,
Jianping Mao,
Yonggang Xing,
Weifeng Liu,
Yuning Cheng,
Renxian Wang,
Yajun Liu,
Xinbao Wu,
Xieyuan Jiang,
Xiaoguang Cheng,
Chi Zhang,
Da-Fu Chen

Affiliations

Jing-Jun Nie: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Bowen Zhang: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China; Department of Radiology, National Center for Orthopaedics, The Fourth Clinical Medical College of Peking University, Beijing Jishuitan Hospital, Beijing, China
Peng Luo: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Maoguo Luo: Biological & Medical Engineering Core Facilities, School of Life Science, Beijing Institute of Technology, Beijing, China
Yuwen Luo: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Jingjing Cao: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Honggang Wang: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Jianping Mao: Department of Spine Surgery, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Yonggang Xing: Department of Spine Surgery, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Weifeng Liu: Department of Orthopaedic Oncology Surgery, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Yuning Cheng: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Renxian Wang: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Yajun Liu: Department of Spine Surgery, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China; Corresponding author.
Xinbao Wu: Department of Orthopedic Trauma, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Xieyuan Jiang: Department of Orthopedic Trauma, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Xiaoguang Cheng: Department of Radiology, National Center for Orthopaedics, The Fourth Clinical Medical College of Peking University, Beijing Jishuitan Hospital, Beijing, China; Corresponding author.
Chi Zhang: Department of Orthopedics, Peking University International Hospital, Beijing, China
Da-Fu Chen: Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China; Corresponding author.

Journal volume & issue: Vol. 38
pp. 455 – 471

Abstract

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Osteosarcoma is the most common malignant bone tumor without efficient management for improving 5-year event-free survival. Immunotherapy is also limited due to its highly immunosuppressive tumor microenvironment (TME). Pore-forming gasdermins (GSDMs)-mediated pyroptosis has gained increasing concern in reshaping TME, however, the expressions and relationships of GSDMs with osteosarcoma remain unclear. Herein, gasdermin E (GSDME) expression is found to be positively correlated with the prognosis and immune infiltration of osteosarcoma patients, and low GSDME expression was observed. A vector termed as LPAD contains abundant hydroxyl groups for hydrating layer formation was then prepared to deliver the GSDME gene to upregulate protein expression in osteosarcoma for efficient TME reshaping via enhanced pyroptosis induction. Atomistic molecular dynamics simulations analysis proved that the hydroxyl groups increased LPAD hydration abilities by enhancing coulombic interaction. The upregulated GSDME expression together with cleaved caspase-3 provided impressive pyroptosis induction. The pyroptosis further initiated proinflammatory cytokines release, increased immune cell infiltration, activated adaptive immune responses and create a favorable immunogenic hot TME. The study not only confirms the role of GSDME in the immune infiltration and prognosis of osteosarcoma, but also provides a promising strategy for the inhibition of osteosarcoma by pore-forming GSDME gene delivery induced enhanced pyroptosis to reshape the TME of osteosarcoma.

Published in Bioactive Materials

ISSN: 2452-199X (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Technology: Electrical engineering. Electronics. Nuclear engineering: Materials of engineering and construction. Mechanics of materials; Science: Biology (General)
Website: https://www.keaipublishing.com/en/journals/bioactive-materials/

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