Zhao Zijian, Sun Fei, Wang Wenyu, Li Bing, Liang Yan, Wei Dengshuai, Sun Yong, Yan Jianqin
Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei 442000, China.
J Control Release. 2025 Jun 21;385:113977. doi: 10.1016/j.jconrel.2025.113977.
Chemotherapeutic drugs such as doxorubicin (DOX) can activate CD8 T cell-mediated antitumor immune responses by inducing immunogenic cell death (ICD), demonstrating the potential of chemo-immune synergistic therapy. However, the continuous stimulation of tumor antigens triggers the exhaustion of CD8 T cells, which has become the main obstacle to inhibiting tumor growth and metastasis. Dual regulation of T cell infiltration and exhaustion to elicit a robust immune response is the key for optimizing tumor immunotherapy. In this study, a membrane-coated framework nucleic acid-based nanogel (RM@NG/DOX) was developed to co-deliver DOX and siRNA (siTOX, thymocyte selection-associated high mobility group box protein, TOX) for the spatiotemporal synergistic regulation of chemo-immunotherapy. This system broke the traditional cationic carrier mode of siRNA delivery and constructed a double-layer barrier to further protect the loaded siTOX and DOX. RM@NG/DOX induced ICD by DOX as an "offensive" signal to enhance T cell infiltration, while siTOX as a "defensive module" reversed the differentiation of exhausted T cells (PD-1 Tim-3) by silencing TOX, a key regulator of T cell exhaustion. Experiments in vitro and in vivo confirmed that RM@NG/DOX reshaped the immune microenvironment through the dual pathway of "activation-reversal" to effectively inhibit tumor growth and metastasis, successfully transforming the "cold tumor" into an immune-infiltrated "hot tumor" and enhancing chemo-immunotherapy. In summary, the combined chemo-genetic nanomedicine based on nucleic acid nanogels provides a new strategy for chemo-immunotherapy and the regulation of T cell exhaustion.
阿霉素（DOX）等化疗药物可通过诱导免疫原性细胞死亡（ICD）激活CD8 T细胞介导的抗肿瘤免疫反应，显示出化学免疫协同治疗的潜力。然而，肿瘤抗原的持续刺激会触发CD8 T细胞耗竭，这已成为抑制肿瘤生长和转移的主要障碍。双重调节T细胞浸润和耗竭以引发强大的免疫反应是优化肿瘤免疫治疗的关键。在本研究中，开发了一种基于膜包被框架核酸的纳米凝胶（RM@NG/DOX），用于共递送DOX和小干扰RNA（siTOX，胸腺细胞选择相关高迁移率族框蛋白，TOX），以实现化学免疫治疗的时空协同调节。该系统打破了传统的小干扰RNA递送阳离子载体模式，并构建了双层屏障以进一步保护负载的siTOX和DOX。RM@NG/DOX以DOX作为“进攻性”信号诱导ICD以增强T细胞浸润，而siTOX作为“防御模块”通过沉默T细胞耗竭的关键调节因子TOX来逆转耗竭T细胞（PD-1 Tim-3）的分化。体外和体内实验证实，RM@NG/DOX通过“激活-逆转”双途径重塑免疫微环境，有效抑制肿瘤生长和转移，成功将“冷肿瘤”转变为免疫浸润的“热肿瘤”并增强化学免疫治疗。总之，基于核酸纳米凝胶的联合化学-基因纳米药物为化学免疫治疗和T细胞耗竭调节提供了一种新策略。
