Stimulator of the interferon genes (STING) pathway is appealing but challenging to potentiate the innate anti-tumor immunity. In this work, nuclear-targeted chimeric peptide nanorods (designated as PFPD) are constructed to amplify innate immunity through localized DNA damage and STING activation. Among which, the chimeric peptide (PpIX-FFVLKPKKKRKV) is fabricated with photosensitizer and nucleus targeting peptide sequence, which can self-assemble into nanorods and load STING agonist of DMXAA. The uniform nanosize distribution and good stability of PFPD improve the sequential targeting delivery of drugs towards tumor cells and nuclei. Under light irradiation, PFPD produce a large amount of reactive oxygen species (ROS) to destroy nuclear DNA , and the released cytosolic DNA fragment will efficiently activate innate anti-tumor immunity in combination with STING agonist. and results indicate the superior ability of PFPD to activate natural killer cells and T cells, thus efficiently eradicating lung metastatic tumor without inducing unwanted side effects. This work provides a sophisticated strategy for localized activation of innate immunity for systemic tumor treatment, which may inspire the rational design of nanomedicine for tumor precision therapy.

中文翻译：

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核靶向嵌合肽纳米棒通过局部 DNA 损伤和 STING 激活来增强先天抗肿瘤免疫力


干扰素基因刺激剂（STING）途径对于增强先天抗肿瘤免疫很有吸引力，但具有挑战性。在这项工作中，构建了核靶向嵌合肽纳米棒（称为 PFPD），通过局部 DNA 损伤和 STING 激活来增强先天免疫。其中，嵌合肽（PpIX-FFVLKPKKKRKV）是用光敏剂和核靶向肽序列构建的，可以自组装成纳米棒并负载DMXAA的STING激动剂。 PFPD均匀的纳米尺寸分布和良好的稳定性改善了药物向肿瘤细胞和细胞核的顺序靶向递送。在光照射下，PFPD产生大量活性氧（ROS）来破坏核DNA，释放的胞质DNA片段与STING激动剂结合将有效激活先天性抗肿瘤免疫。结果表明，PFPD 具有激活自然杀伤细胞和 T 细胞的卓越能力，从而有效根除肺转移肿瘤，且不会引起不良副作用。这项工作为全身肿瘤治疗的先天免疫局部激活提供了复杂的策略，这可能会启发肿瘤精准治疗纳米医学的合理设计。