Li Yanjie, Feng Hanxin, Yang Huang, Wang Yi, Ding Yuan, Mao Zhengwei, Du Yang, Wang Weilin
Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, 310009, China.
Adv Healthc Mater. 2025 Apr;14(11):e2500610. doi: 10.1002/adhm.202500610. Epub 2025 Mar 12.
Pyroptosis, a form of programmed cell death mediated by the gasdermin family, has emerged as a promising strategy for inducing anti-tumor immunity. However, efficiently inducing pyroptosis in tumor cells remains a significant challenge due to the limited activation of key mediators like caspases in tumor tissues. Herein, a self-priming pyroptosis-inducing agent (MnNZ@OMV) is developed by integrating outer membrane vesicles (OMVs) with manganese dioxide nanozymes (MnNZ) to trigger pyroptosis in tumor cells. OMVs, derived from Escherichia coli, are coated onto spiny MnNZ to prepare MnNZ@OMV. Once internalized by tumor cells, MnNZ@OMV responds to elevated intracellular glutathione (GSH) levels, releasing Mn⁺ and OMV components. This leads to GSH depletion and Mn⁺-catalyzed reactive oxygen species generation, which triggers NF-κB translocation and prime caspase-11 expression. Subsequently, lipopolysaccharides from OMVs activate caspase-11, resulting in GSDMD cleavage and pyroptosis induction. MnNZ@OMV significantly induces tumor pyroptosis in vivo, promoting dendritic cell maturation and CD8⁺ T cell activation, leading to robust anti-tumor effects. Collectively, this study presents a novel self-priming approach for inducing tumor cell pyroptosis through the noncanonical caspase-11/GSDMD pathway, offering a promising avenue for future cancer immunotherapy.
细胞焦亡是一种由gasdermin家族介导的程序性细胞死亡形式，已成为诱导抗肿瘤免疫的一种有前景的策略。然而，由于肿瘤组织中半胱天冬酶等关键介质的激活有限，在肿瘤细胞中有效诱导细胞焦亡仍然是一项重大挑战。在此，通过将外膜囊泡（OMV）与二氧化锰纳米酶（MnNZ）整合，开发了一种自启动的细胞焦亡诱导剂（MnNZ@OMV），以触发肿瘤细胞中的细胞焦亡。源自大肠杆菌的OMV被包裹在多刺的MnNZ上以制备MnNZ@OMV。一旦被肿瘤细胞内化，MnNZ@OMV会对细胞内谷胱甘肽（GSH）水平升高做出反应，释放Mn⁺和OMV成分。这导致GSH耗竭和Mn⁺催化的活性氧生成，从而触发NF-κB易位并启动半胱天冬酶-11的表达。随后，来自OMV的脂多糖激活半胱天冬酶-11，导致GSDMD裂解并诱导细胞焦亡。MnNZ@OMV在体内显著诱导肿瘤细胞焦亡，促进树突状细胞成熟和CD8⁺T细胞活化，从而产生强大的抗肿瘤作用。总的来说，这项研究提出了一种通过非经典半胱天冬酶-11/GSDMD途径诱导肿瘤细胞焦亡的新型自启动方法，为未来的癌症免疫治疗提供了一条有前景的途径。
