Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Orthopedics Research Institute of Zhejiang University, Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Clinical Research Center of Motor System Disease of Zhejiang Province, 88 Jiefang Road, Hangzhou City, Zhejiang Province, 310003, P. R. China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Adv Mater. 2023 Dec;35(51):e2304296. doi: 10.1002/adma.202304296. Epub 2023 Oct 27.
Tumor-associated macrophage (TAM) reprogramming is a promising therapeutic approach for cancer immunotherapy; however, its efficacy remains modest due to the low bioactivity of the recombinant cytokines used for TAM reprogramming. mRNA therapeutics are capable of generating fully functional proteins for various therapeutic purposes but accused for its poor sustainability. Inspired by kinetic energy recovery systems (KERS) in hybrid vehicles, a cytokine efficacy recovery system (CERS) is designed to substantially augment the therapeutic index of mRNA-based tumor immunotherapy via a "capture and stabilize" mechanism exerted by a nanostructured mineral coating carrying therapeutic cytokine mRNA. CERS remarkably recycles nearly 40% expressed cytokines by capturing them onto the mineral coating to extend its therapeutic timeframe, further polarizing the macrophages to strengthen their tumoricidal activity and activate adaptive immunity against tumors. Notably, interferon-γ (IFN-γ) produced by CERS exhibits ≈42-fold higher biological activity than recombinant IFN-γ, remarkably decreasing the required IFN-γ dosage for TAM reprogramming. In tumor-bearing mice, IFN-γ cmRNA@CERS effectively polarizes TAMs to inhibit osteosarcoma progression. When combined with the PD-L1 monoclonal antibody, IFN-γ cmRNA@CERS significantly boosts antitumor immune responses, and substantially prevents malignant lung metastases. Thus, CERS-mediated mRNA delivery represents a promising strategy to boost antitumor immunity for tumor treatment.
肿瘤相关巨噬细胞（TAM）重编程是癌症免疫治疗的一种很有前途的治疗方法；然而，由于用于 TAM 重编程的重组细胞因子的生物活性低，其疗效仍然有限。mRNA 疗法能够为各种治疗目的产生具有完全功能的蛋白质，但因其可持续性差而受到指责。受混合动力汽车中的动能回收系统（KERS）的启发，设计了一种细胞因子效力恢复系统（CERS），通过携带治疗性细胞因子 mRNA 的纳米结构矿物涂层施加的“捕获和稳定”机制，显著提高基于 mRNA 的肿瘤免疫疗法的治疗指数。CERS 通过将它们捕获到矿物涂层上来显著回收近 40%表达的细胞因子，从而延长其治疗时间框架，进一步将巨噬细胞极化为增强其杀肿瘤活性并激活针对肿瘤的适应性免疫。值得注意的是，CERS 产生的干扰素-γ（IFN-γ）的生物学活性比重组 IFN-γ高约 42 倍，显著降低了 TAM 重编程所需的 IFN-γ 剂量。在荷瘤小鼠中，IFN-γ cmRNA@CERS 有效极化 TAMs 以抑制骨肉瘤进展。当与 PD-L1 单克隆抗体联合使用时，IFN-γ cmRNA@CERS 显著增强了抗肿瘤免疫反应，并显著防止了恶性肺转移。因此，CERS 介导的 mRNA 递送来增强抗肿瘤免疫以进行肿瘤治疗是一种很有前途的策略。
