Gül Sezen, Vergnaud Juliette, Fay François, Fattal Elias
Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, Orsay, 91400, France.
Drug Deliv Transl Res. 2025 Sep 18. doi: 10.1007/s13346-025-01970-1.
Tumor-associated macrophages (TAMs) represent solid tumors' most prevalent immune cell subset. These cells primarily adopt an immunosuppressive phenotype in the tumor microenvironment, promoting tumor initiation and progression. Their ability to shift between distinct activation states identifies TAMs as ideal targets for cancer treatment. Consequently, reprogramming TAMs from an immunosuppressive to an immunostimulatory state has emerged as a promising therapeutic approach to fight cancer. RNA interference has gained significant attention as a therapeutic modality due to its potential to selectively inhibit the expression of one or several critical proteins for the pro-tumorous activities of TAMs. However, the efficiency of RNA interference is limited by its susceptibility to nuclease degradation, rapid clearance from the body, and poor cellular uptake. These limitations necessitate the development of delivery systems to enhance their therapeutic potential. Among the nanocarriers we discuss in this review, lipid nanoparticles (LNPs) have been widely recognized as the most effective for siRNA or miRNA, providing stability, high gene silencing efficiency, and biocompatibility. The clinical application of LNPs has been further advanced by recent progress in microfluidics, enabling reproducible and scalable production of LNPs with high encapsulation efficiency. The increasing number of preclinical studies shows the growing interest in cancer immunotherapy using RNA interference-LNPs. In this review, we summarize the current knowledge on macrophage biology and its role in cancer, explore advancements in RNA interference-LNP technology, review ongoing research efforts, and discuss key translational challenges that must be addressed for the clinical success of RNA interference-LNP-based macrophage reprogramming.
肿瘤相关巨噬细胞（TAMs）是实体瘤中最普遍的免疫细胞亚群。这些细胞在肿瘤微环境中主要呈现免疫抑制表型，促进肿瘤的起始和进展。它们在不同激活状态之间转换的能力使TAMs成为癌症治疗的理想靶点。因此，将TAMs从免疫抑制状态重编程为免疫刺激状态已成为一种有前景的抗癌治疗方法。RNA干扰作为一种治疗方式受到了广泛关注，因为它有潜力选择性抑制TAMs促肿瘤活性的一种或几种关键蛋白的表达。然而，RNA干扰的效率受到其易被核酸酶降解、从体内快速清除以及细胞摄取不佳的限制。这些限制使得开发递送系统以增强其治疗潜力成为必要。在我们本次综述中讨论的纳米载体中，脂质纳米颗粒（LNPs）已被广泛认为是对siRNA或miRNA最有效的载体，具有稳定性、高基因沉默效率和生物相容性。微流控技术的最新进展进一步推动了LNPs的临床应用，能够以高封装效率可重复且可扩展地生产LNPs。越来越多的临床前研究表明，人们对使用RNA干扰-LNPs进行癌症免疫治疗的兴趣日益浓厚。在本综述中，我们总结了关于巨噬细胞生物学及其在癌症中的作用的现有知识，探讨了RNA干扰-LNP技术的进展，回顾了正在进行的研究工作，并讨论了基于RNA干扰-LNP的巨噬细胞重编程临床成功必须解决的关键转化挑战。
