Precision engineering of macrophage reprogramming with RNA interference-loaded lipid nanoparticles: a game-changer in cancer immunotherapy

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.