Ferroptosis has the potential to induce powerful antitumor immunity by activating immunogenic cell death (ICD) of tumor cells. However, achieving precise and effective ferroptosis-immunotherapy remains challenging. Herein, a biomimetic metal-phenolic networks (MPNs) nanosystem was proposed for codelivery of Cas9 ribonucleoprotein (RNP) and DNAzyme systems to achieve robust synergistic ferroptosis-immunotherapy. The nanosystem was consisted of MPNs containing tannic acid (TA) and Fe³⁺ ions, the Cas9 RNP and DNAzyme systems, which were released and exerted their respective functions after intracellular delivery with the aid of erythrocyte membrane camouflage. The Fe²⁺ ions were produced from Fe³⁺ by TA reduction to assist in endosomal escape and induced ferroptosis. Cas9 RNP entered into the nucleus and executed gene editing of GPX4 to enhance ferroptosis and thus induce ICD. Simultaneously, Fe²⁺ assisted DNAzyme system was activated to silence GPR65 gene expression to further achieve synergistic ferroptosis-immune responses, resulting in the eradication of both orthotopic and pulmonary metastatic tumors. Overall, this biomimetic nanosystem provides a versatile strategy for synergistic gene editing, ferroptosis, and immunotherapy to achieve robust ferroptosis-immunotherapy.

中文翻译：

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仿生 Fe3+ 金属酚类网络使 DNAzyme 和 Cas9 RNP 递送能够协同肿瘤铁死亡免疫疗法


铁死亡有可能通过激活肿瘤细胞的免疫原性细胞死亡 （ICD） 来诱导强大的抗肿瘤免疫。然而，实现精确有效的铁死亡免疫疗法仍然具有挑战性。在此，提出了一种仿生金属酚类网络 （MPN） 纳米系统，用于 Cas9 核糖核蛋白 （RNP） 和 DNAzyme 系统的共同递送，以实现稳健的协同铁死亡-免疫疗法。纳米系统由含有单宁酸 （TA） 和 Fe³⁺ 离子的 MPN、Cas9 RNP 和 DNAzyme 系统组成，它们在红细胞膜伪装的帮助下在细胞内递送后被释放并发挥各自的功能。Fe²⁺ 离子是通过 TA 还原从 Fe³⁺ 产生的，以帮助内体逃逸和诱导铁死亡。Cas9 RNP 进入细胞核并执行 GPX4 的基因编辑以增强铁死亡，从而诱导 ICD。同时，激活 Fe²⁺ 辅助 DNAzyme 系统以沉默 GPR65 基因表达，以进一步实现协同铁死亡免疫反应，从而根除原位和肺转移性肿瘤。总体而言，这种仿生纳米系统为协同基因编辑、铁死亡和免疫疗法提供了一种多功能策略，以实现稳健的铁死亡-免疫疗法。