Synchronously Delivering Melittin and Evoking Ferroptosis via Tumor Microenvironment-Triggered Self-Destructive Metal-Organic Frameworks to Boost Cancer Immunotherapy

被引:0
作者
Zhang, Dongsheng [1 ]
Wang, Tingting [1 ]
Zhang, Xun [1 ]
Xu, Yuting [1 ]
Ming, Jiang [3 ]
Wang, Xiaoxiao [1 ]
Liu, Zhenfeng [1 ]
Li, Jingchao [2 ]
Su, Xinhui [1 ]
机构
[1] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Dept Nucl Med, Hangzhou 310003, Peoples R China
[2] Army Med Univ, Daping Hosp, Dept Nucl Med, Chongqing 400042, Peoples R China
[3] Xiamen Univ, Coll Chem & Chem Engn, State Key Lab Phys Chem Solid Surfaces, Xiamen 361102, Peoples R China
基金
中国国家自然科学基金;
关键词
drug delivery; ferroptosis; immunotherapy; melittin; metal-organic frameworks; EXOSOMES;
D O I
10.1002/adhm.202500003
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
The primary goal of treating malignant tumors is to efficiently eliminate the primary tumor and prevent metastasis and recurrence. Unfortunately, the immunosuppressive tumor microenvironment (TME) is a significant obstacle to effective oncotherapy. Herein, a therapeutic strategy based on melittin (MLT) encapsulated in hyaluronic acid-modified metal-organic frameworks (MOFs) is pioneered, focusing on the safe delivery and TME-responsive release of MLT to reshaping the immunosuppressive TME and simultaneously activating the immune system to eradicate cancerous cells. Iron-based MOFs respond to glutathione and pH, degrade within a moderately acidic TME, and achieve tumor-specific release of MLT. Additionally, the iron-mediated Fenton reaction produces reactive oxygen species that augment oxidative stress, ultimately leading to tumor-specific ferroptosis, whereas MLT-induced membrane disruption promotes immunogenic cell death to activate the immune system. In combination with the immune checkpoint inhibitor anti-PD-L1, this nanodrug elicits potent antitumor immune responses, facilitating the infiltration of effector T cells and enhancing systemic antitumor T cell immunity to suppress both primary and distant tumors. This study demonstrates the tremendous potential of nanoscale self-destructive MOFs for the targeted transport and controlled release of MLT and reveals the promoting effect of combined MLT and ferroptosis delivery on cancer immunotherapy.
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页数:14
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