白细胞介素-12 (IL-12) 是一种重要的细胞因子，具有显着的抗癌特性，包括增强 T 细胞介导的癌细胞杀伤作用和抑制肿瘤血管生成。迄今为止，许多方法都经过评估，以实现 IL-12 的原位过度表达，最大限度地减少泄漏和随之而来的毒性。在这里，它的重点是环状单链DNA（Css DNA），这是一种以其独特结构为特征的DNA，可以在哺乳动物中表达。发现Css DNA肌肉注射可诱导持续半年的荧光素酶表达，瘤内注射显示出有效的抗肿瘤效果。受这些发现的启发，现在开发了叶酸修饰的 LNP 系统，用于递送表达 IL-12 的 Css DNA，用于治疗 4T1 三阴性乳腺癌 (TNBC)。该递送系统有效激活抗癌免疫反应，减缓肿瘤生长，显着延长动物模型的生存期，并防止肿瘤复发。经过6个月的长期观察，治愈小鼠的淋巴结和血清中仍可检测到升高的IL-12水平。这项研究强调了 Css DNA 的长期持续表达能力及其抑制复发的能力，以及肿瘤靶向 LNP 用于基于 Css DNA 的癌症治疗的潜力，为基因过表达策略提供了新的见解。© 2024 Wiley‐VCH有限公司。

Interleukin-12 (IL-12) is a critical cytokine with notable anticancer properties, including enhancing T-cell-mediated cancer cell killing, and curbing tumor angiogenesis. To date, many approaches are evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Here, it is focused on circular single-stranded DNA (Css DNA), a type of DNA characterized by its unique structure, which could be expressed in mammals. It is discovered that Css DNA can induce sustained luciferase expression for half a year by intramuscular injection and showed effective antitumor results by intratumoral injection. Motivated by these findings, a folate-modified LNP system is now developed for the delivery of Css DNA expressing IL-12 for the therapy of 4T1 triple-negative breast cancer (TNBC). This delivery system effectively activates anti-cancer immune responses, slows tumor growth, significantly prolongs survival in animal models, and prevents tumor recurrence. After 6 months of long-term observation, the elevated level of IL-12 is still detectable in the lymph nodes and serum of the cured mice. This study highlights the long-term sustained expression capacity of Css DNA and its ability to inhibit recurrence, and the potential of tumor-targeted LNPs for Css DNA-based cancer therapy, providing a new insight into gene overexpression strategy.© 2024 Wiley‐VCH GmbH.