Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Dermatology and Venereology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Department of Dermatology, Shangqiu People's Hospital, Shangqiu, Henan 221004, China.
Department of Dermatology, The Affiliated Huaian No 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu 223300, China.
Acta Biomater. 2024 Oct 15;188:329-343. doi: 10.1016/j.actbio.2024.09.015. Epub 2024 Sep 13.
The regulation of intracellular ionic homeostasis to trigger antigen-specific immune responses has attracted extensive interest in tumor therapy. In this study, we developed a dual-pathway nanoreactor, Au-CuSe@ZIF-8@P18 NPs (ACS-Z-P NPs), which targets danger-associated molecular patterns (DAMPs) and releases Zn and reactive oxygen species (ROS) within the tumor microenvironment (TME). Zn released from the metal-organic frameworks (MOFs) was deposited in the cytoplasm, leading to aberrant transcription levels of intracellular zinc-regulated proteins and DNA damage, thereby inducing pyroptosis and immunogenic cell death (ICD) dependent on caspase1/gasdermin D (GSDMD) pathway. Furthermore, upon laser irradiation, ACS-Z-P NPs could break through the limitations of inherent defects of immunosuppression in TME, enhance ROS generation through a Fenton-like reaction cascade, which subsequently triggered the activation of inflammatory vesicles and the release of damage-associated molecular patterns (DAMPs). This cascade effect led to the amplification of pyroptosis and immunogenic cell death (ICD), thereby remodeling the immunosuppressed TME. Consequently, this process improved dendritic cell (DC) antigen presentation and augmented anti-tumor T-cell responses, effectively initiating antigen-specific immune responses and further enhancing pyroptosis and ICD. This study explores the therapeutic properties of these mechanisms in detail. STATEMENT OF SIGNIFICANCE: The synthesized Au-CuSe@ZIF-8@P18 nanoparticles (ACS-Z-Ps) can effectively enhance the body's immune response by regulating zinc ion levels within cells. This regulation leads to abnormal levels of zinc-regulated protein transcription and DNA damage, which induces cellular pyroptosis. As a result, antigen presentation to dendritic cells (DCs) is improved, and anti-tumor T-cell responses are enhanced. The ACS-Z-P NPs overcome the limitations of ROS deficiency and immunosuppression in the tumor microenvironment by using HO in the tumor microenvironment through a Fenton-like reaction. This leads to an increased production of ROS and O, remodeling of the immunosuppressed tumor microenvironment, and enhanced induction of cell pyroptosis and immunogenic cell death. ACS-Z-P NPs targeted B16 cells using the photosensitizer P18 in combination with PDT treatment. This approach significantly inhibited the proliferation of B16 cells and effectively inhibited tumor growth.
细胞内离子稳态的调节触发针对肿瘤的特异性免疫反应，这在肿瘤治疗中引起了广泛关注。在这项研究中，我们开发了一种双途径纳米反应器，Au-CuSe@ZIF-8@P18 NPs（ACS-Z-P NPs），它靶向危险相关分子模式（DAMPs），并在肿瘤微环境（TME）中释放锌和活性氧（ROS）。金属有机骨架（MOFs）释放的锌沉积在细胞质中，导致细胞内锌调节蛋白的转录水平异常和 DNA 损伤，从而诱导依赖半胱天冬酶 1/气穴蛋白 D（GSDMD）途径的细胞焦亡和免疫原性细胞死亡（ICD）。此外，在激光照射下，ACS-Z-P NPs 可以突破 TME 中固有免疫抑制缺陷的限制，通过芬顿样反应级联增强 ROS 的产生，随后触发炎症小体的激活和损伤相关分子模式（DAMPs）的释放。这种级联效应导致细胞焦亡和免疫原性细胞死亡（ICD）的放大，从而重塑免疫抑制的 TME。因此，该过程增强了树突状细胞（DC）的抗原呈递并增强了抗肿瘤 T 细胞反应，有效引发针对肿瘤的特异性免疫反应，并进一步增强细胞焦亡和 ICD。本研究详细探讨了这些机制的治疗特性。
意义声明：合成的 Au-CuSe@ZIF-8@P18 纳米粒子（ACS-Z-Ps）可以通过调节细胞内锌离子水平有效增强机体的免疫反应。这种调节导致锌调节蛋白转录和 DNA 损伤异常，从而诱导细胞焦亡。结果，抗原呈递给树突状细胞（DC）得到改善，抗肿瘤 T 细胞反应增强。ACS-Z-P NPs 通过 Fenton 样反应利用肿瘤微环境中的 HO 来克服肿瘤微环境中 ROS 缺乏和免疫抑制的局限性。这导致 ROS 和 O 的产生增加，重塑免疫抑制的肿瘤微环境，并增强细胞焦亡和免疫原性细胞死亡的诱导。ACS-Z-P NPs 与 PDT 治疗相结合，使用光敏剂 P18 靶向 B16 细胞。这种方法显著抑制了 B16 细胞的增殖，并有效抑制了肿瘤的生长。
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