“Multi‐in‐One” Yolk‐Shell Structured Nanoplatform Inducing Pyroptosis and Antitumor Immune Response Through Cascade Reactions

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2024-07, Vol.20 (30), p.e2400254-n/a
• Main Authors: Wang, Yu‐Ying, Li, Shu‐Lan, Zhang, Xiao‐Yang, Jiang, Feng‐Lei, Guo, Qing‐Lian, Jiang, Peng, Liu, Yi
• Format: Article
• Language: English
• Subjects: Animals; Cascade chemical reactions; cascade reactions; Cell death; Cell Line, Tumor; chemodynamic therapy; Copper; Copper - chemistry; cuproptosis; Damage patterns; Glucose oxidase; Glucose Oxidase - chemistry; Glucose Oxidase - metabolism; Humans; Hydrogen peroxide; Hydrogen Peroxide - chemistry; Imidazoles; Immune system; Immunity - drug effects; immunogenic cell death; Metal-organic frameworks; Metal-Organic Frameworks - chemistry; Metal-Organic Frameworks - pharmacology; Mice; Nanoparticles - chemistry; Oxidative Stress - drug effects; pyroptosis; Pyroptosis - drug effects; Reactive Oxygen Species - metabolism; Tumor Microenvironment - drug effects; Zeolites
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.202400254

Pyroptosis, a new mode of regulatory cell death, holds a promising prospect in tumor therapy. The occurrence of pyroptosis can trigger the release of damage‐associated molecular patterns (DAMPs) and activate the antitumor immune response. Moreover, enhancing intracellular reactive oxygen species (ROS) generation can effectively induce pyroptosis. Herein, an integrated nanoplatform (hCZAG) based on zeolitic imidazolate framework‐8 (ZIF‐8) with Cu2+ and Zn2+ as active nodes and glucose oxidase (GOx) loading is constructed to evoke pyroptosis. GOx can effectively elevate intracellular hydrogen peroxide (H2O2) levels to regulate the unfavorable tumor microenvironment (TME). Cu2+ can be reduced to Cu+ by endogenous overexpressed GSH and both Cu2+ and Cu+ can exert Fenton‐like activity to promote ROS generation and amplify oxidative stress. In addition, the accumulation of Cu2+ leads to the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), thus resulting in cuproptosis. Notably, the outburst of ROS induced by hCZAG activates Caspase‐1 proteins, leads to the cleavage of gasdermin D (GSDMD), and induces pyroptosis. Pyroptosis further elicits an adaptive immune response, leading to immunogenic cell death (ICD). This study provides effective strategies for triggering pyroptosis‐mediated immunotherapy and achieving improved therapeutic effects. Yolk‐shell nanostructured hCZAG with Cu2+ and Zn2+ as active nodes and GOx‐loading are successfully constructed. hCZAG can enhance ROS generation through chemodynamic therapy (CDT) and cuproptosis via cascade reactions. The accumulation of ROS induces pyroptosis, which can further activate immune response by promoting the release of damage‐associated molecular patterns (DAMPs). Thus, the integrated nanoplatform can achieve remarkable antitumor efficacy.