Sonodynamic therapy (SDT) is demonstrated to trigger the systemic immune response of the organism and facilitate the treatment of metastatic tumors. However, SDT‐mediated neutrophil extracellular traps (NETs) formation can promote tumor cell spread, thus weakening the therapeutic effectiveness of metastatic tumors. Herein, the amorphous CoW‐layered double hydroxide (a‐CoW‐LDH) nanosheets are functionalized with a peptidyl arginine deiminase 4 (PAD4) inhibitor, i.e., YW3‐56, to construct a multifunctional nanoagent (a‐LDH@356) for synergistic SDT/immunotherapy. Specifically, a‐CoW‐LDH nanosheets can act as a sonosensitizer to generate abundant reactive oxygen species (ROS) under US irradiation. After loading with YW3‐56, a‐LDH@356 plus US irradiation not only effectively induces ROS generation and immunogenic cell death, but also inhibits the elevation of citrullinated histone H3 (H3cit) and the release of NETs, enabling a synergistic enhancement of anti‐tumor metastasis effect. Using 4T1 tumor model, it is demonstrated that combining a‐CoW‐LDH with YW3‐56 stimulates an anti‐tumor response by upregulating the proportion of immune‐activated cells and inducing polarization of M1 macrophages, and inhibits immune escape by downregulating the expression of PD‐1 on immune cells under US irradiation, which not only arrests primary tumor progression with a tumor inhibition rate of 69.5% but also prevents tumor metastasis with the least number of lung metastatic nodules.

中文翻译：

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PAD4抑制剂功能化层状双氢氧化物纳米片用于肿瘤转移的协同声动力疗法/免疫疗法

声动力疗法（SDT）被证明可以触发生物体的全身免疫反应并促进转移性肿瘤的治疗。然而，SDT介导的中性粒细胞胞外陷阱（NET）的形成可以促进肿瘤细胞扩散，从而削弱转移性肿瘤的治疗效果。在此，将无定形CoW层状双氢氧化物（a-CoW-LDH）纳米片用肽基精氨酸脱亚胺酶4（PAD4）抑制剂（即YW3-56）功能化，构建多功能纳米剂（a-LDH@356）以实现协同作用SDT/免疫疗法。具体来说，a-CoW-LDH 纳米片可以作为声敏剂，在超声波照射下产生丰富的活性氧（ROS）。负载 YW3-56 后，a-LDH@356 加上 US 照射不仅能有效诱导 ROS 生成和免疫原性细胞死亡，而且还能抑制瓜氨酸组蛋白 H3 (H3cit) 的升高和 NETs 的释放，从而协同增强抗‐肿瘤转移作用。使用4T1肿瘤模型，证明a-CoW-LDH与YW3-56组合可通过上调免疫激活细胞的比例并诱导M1巨噬细胞极化来刺激抗肿瘤反应，并通过下调免疫逃逸的表达来抑制免疫逃逸。在US照射下PD-1作用于免疫细胞，不仅可以阻止原发性肿瘤进展，肿瘤抑制率为69.5%，而且可以阻止肿瘤转移，肺转移结节数量最少。