Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limits clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno-associated virus DNA using coat proteins from a tumour-targeted bacteriophage (phage). We show that Transmorphic Phage/AAV (TPA) particles provide superior delivery of transgenes over current phage-derived vectors through greater diffusion across the extracellular space and improved intracellular trafficking. We used TPA to target the delivery of cytokine-encoding transgenes for interleukin-12 (IL12), and novel isoforms of IL15 and tumour necrosis factor alpha (TNF$\alpha$) for tumour immunotherapy. Our results demonstrate selective and efficient gene delivery and immunotherapy against solid tumours in vivo, without harming healthy organs. Our transmorphic particle system provides a promising modality for safe and effective gene delivery, and cancer immunotherapies through cross-species complementation of two commonly used viruses.

中文翻译：

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使用变形粒子的系统性靶向癌症免疫治疗和基因传递

免疫疗法是癌症治疗的有力工具，但细胞因子和免疫剂的多效性极大地限制了临床转化和安全性。为了解决这一未满足的需求，我们通过使用来自肿瘤靶向噬菌体（噬菌体）的外壳蛋白对人重组腺相关病毒 DNA 进行变形包裹，设计并表征了一种系统靶向细胞因子基因递送系统。我们表明，与目前的噬菌体衍生载体相比，Transmorphic Phage/AAV (TPA) 颗粒通过在细胞外空间的更大扩散和改进的细胞内运输提供了更好的转基因递送。我们使用 TPA 靶向传递白细胞介素 12 (IL12) 的细胞因子编码转基因，以及 IL15 和肿瘤坏死因子 α (TNF) 的新型同种型$\alpha$) 用于肿瘤免疫治疗。我们的研究结果表明，在不损害健康器官的情况下，选择性和有效的基因递送和体内实体瘤免疫治疗。我们的变形粒子系统通过两种常用病毒的跨物种互补，为安全有效的基因传递和癌症免疫疗法提供了一种有前景的方式。