Tumor-targeting hydroxyapatite nanoparticles for remodeling tumor immune microenvironment (TIME) by activating mitoDNA-pyroptosis pathway in cancer.

Autor: Yang Y; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Yang J; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China.; Department of General Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China., Zhu N; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Qiu H; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Feng W; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Chen Y; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Chen X; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Chen Y; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Zheng W; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China., Liang M; Department of Oncology, Innovation Centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. 2015687053@gzhmu.edu.cn., Lin T; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China. lintian108@163.com., Yu J; Department of General Surgery, Nanfang Hospital, Southern medical University, Guangzhou, 510515, China. balbc@163.com., Guo Z; Breast Division, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. zzguo81@163.com.
Jazyk: angličtina
Zdroj: Journal of nanobiotechnology [J Nanobiotechnology] 2023 Dec 07; Vol. 21 (1), pp. 470. Date of Electronic Publication: 2023 Dec 07.
DOI: 10.1186/s12951-023-02231-4
Abstrakt: In recent years, immunotherapy has emerged as a promising strategy for treating solid tumors, although its efficacy remains limited to a subset of patients. Transforming non-responsive "cold" tumor types into immuno-responsive "hot" ones is critical to enhance the efficacy of immune-based cancer treatments. Pyroptosis, a programmed cell death mechanism, not only effectively eliminates tumor cells but also triggers a potent inflammatory response to initiate anti-tumor immune activities. This sheds light on the potential of pyroptosis to sensitize tumors to immune therapy. Hence, it is urgent to explore and develop novel treatments (e.g., nanomedicines) which are capable of inducing pyroptosis. In this study, we constructed tumor-targeting nanoparticles (CS-HAP@ATO NPs) by loading atorvastatin (ATO) onto chondroitin sulfate (CS) modified hydroxyapatite (HAP) nanoparticles (CS-HAP). CS was strategically employed to target tumor cells, while HAP exhibited the capacity to release calcium ions (Ca 2+ ) in response to the tumor microenvironment. Moreover, ATO disrupted the mitochondrial function, leading to intracellular energy depletion and consequential changes in mitochondrial membrane permeability, followed by the influx of Ca 2+ into the cytoplasm and mitochondria. CS and HAP synergetically augmented mitochondrial calcium overload, inciting the production of substantial amount of reactive oxygen species (ROS) and the subsequent liberation of oxidized mitochondrial DNA (OX-mitoDNA). This intricate activation process promoted the assembly of inflammasomes, most notably the NLRP3 inflammasome, followed by triggering caspase-1 activation. The activated caspase-1 was able to induce gasderminD (GSDMD) protein cleavage and present the GSDM-N domain, which interacted with phospholipids in the cell membrane. Then, the cell membrane permeability was raised, cellular swelling was observed, and abundant cell contents and inflammatory mediators were released. Ultimately, this orchestrated sequence of events served to enhance the anti-tumor immunoresponse within the organism.
(© 2023. The Author(s).)
Databáze: MEDLINE
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