Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China; Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China.
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences; Shanghai Research Center of Ophthalmology and Optometry, Shanghai 200030, China.
Biomaterials. 2024 Dec;311:122710. doi: 10.1016/j.biomaterials.2024.122710. Epub 2024 Jul 21.
Low-expression antigens, especially neoantigens, pose a significant challenge in immunotherapy for low immunogenicity pancreatic cancer. Increasing the tumor mutation burden is crucial to enhance the expression of tumor antigens and improve tumor immunogenicity. However, the incomplete intervention in DNA stability hampers effective elevation of the tumor mutation burden, thus reducing the probability of neoantigen. To address this issue, we have developed a novel nano-regulator that intervenes in the DNA stability of tumor cells, thereby enhancing tumor mutations. This nano-regulator comprises metal-organic frameworks (MOFs) encapsulating DNA damage agent doxorubicin and DNA damage repair inhibitor siRNA-ATR, enabling simultaneous induction of DNA mutations and inhibition of their repair. Importantly, this regulator, named as MOF, can modulate the tumor gene expression profile, induce the production of neoantigens of Atp8b1, and enhance the immunogenicity of pancreatic cancer. The characteristics of DNA stability intervention by MOF hold promise for augmenting the immune response in low immunogenic tumors, making it a potential nanomedicine for the treatment of pancreatic cancer.
低表达抗原，尤其是新抗原，给低免疫原性胰腺癌的免疫治疗带来了巨大挑战。提高肿瘤突变负担对于增强肿瘤抗原的表达和提高肿瘤免疫原性至关重要。然而，DNA 稳定性的不完全干预会阻碍肿瘤突变负担的有效提高，从而降低新抗原的概率。为了解决这个问题，我们开发了一种新型的纳米调节剂，可以干预肿瘤细胞的 DNA 稳定性，从而增强肿瘤突变。这种纳米调节剂由金属有机骨架（MOFs）包裹的 DNA 损伤剂阿霉素和 DNA 损伤修复抑制剂 siRNA-ATR 组成，能够同时诱导 DNA 突变和抑制其修复。重要的是，这种名为 MOF 的调节剂可以调节肿瘤基因表达谱，诱导 Atp8b1 新抗原的产生，并增强胰腺癌的免疫原性。MOF 对 DNA 稳定性的干预特性有望增强低免疫原性肿瘤的免疫反应，使其成为治疗胰腺癌的一种有潜力的纳米药物。
