Lei Sibei, Gao Yan, Wang Kaiyu, Wu Shan, Zhu Manfang, Chen Xiaohua, Zhou Weilin, Chen Xiayu, Zhang Jin, Duan Xingmei, Men Ke
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
ACS Nano. 2025 May 13;19(18):17653-17673. doi: 10.1021/acsnano.5c01366. Epub 2025 Apr 30.
Gene therapies and adoptive cell therapy (ACT) are promising strategies for cancer immunotherapy. Referring to their different mechanisms, the combination of these two might result in a strategy with potential collaborative and compensatory effects. However, it is challenging to combine gene therapies and ACT that work in a proper logical order. Here, we developed a double-layered spherical scaffold (DLS) to codeliver mRNA and T cells and constructed an implantable hydrogel formulation, named the GD-920 scaffold. With a diameter of 7 mm, this scaffold loaded primary T cells in the inner layer and the Bim mRNA nanocomplex in the outer layer. While maintaining their bioactivities, GD-920 released gene and cell payloads in a controllable and sequential manner. The mRNA complex from the outer layer was first released and induced immunogenic tumor cell death. The produced antigens then migrated into the scaffold with dendritic cells, triggering a tumor-specific immune response. Finally, activated T cells released by the inner layer attacked the tumor tissue via massive infiltration. We showed that in situ implantation of the GD-920 scaffold is capable of effectively inhibiting tumor growth and is far more potent than that of control scaffolds containing a single payload. Our results demonstrated the outstanding potential of this DLS in combining gene and cell therapeutic approaches to cancer immunotherapy.
基因疗法和过继性细胞疗法（ACT）是癌症免疫治疗中很有前景的策略。鉴于它们不同的作用机制，将这两种疗法结合可能会产生具有潜在协同和补偿作用的策略。然而，要以合理的逻辑顺序将基因疗法和ACT结合起来具有挑战性。在此，我们开发了一种双层球形支架（DLS）来共递送信使核糖核酸（mRNA）和T细胞，并构建了一种可植入的水凝胶制剂，命名为GD-920支架。这种直径为7毫米的支架在内层装载原代T细胞，在外层装载Bim mRNA纳米复合物。在保持其生物活性的同时，GD-920以可控且有序的方式释放基因和细胞负载物。外层的mRNA复合物首先释放并诱导免疫原性肿瘤细胞死亡。产生的抗原随后与树突状细胞一起迁移到支架中，引发肿瘤特异性免疫反应。最后，内层释放的活化T细胞通过大量浸润攻击肿瘤组织。我们表明，原位植入GD-920支架能够有效抑制肿瘤生长，且比含有单一负载物的对照支架更有效。我们的结果证明了这种DLS在将基因和细胞治疗方法结合用于癌症免疫治疗方面具有出色的潜力。
