Nano-immunotherapeutic strategies for targeted RNA delivery: Emphasizing the role of monocyte/macrophages as nanovehicles to treat glioblastoma multiforme

Glioblastoma multiforme (GBM) is considered the most aggressive and heterogeneous type of brain malignancy. The substantial invasion of the central nervous system parenchyma is a typical hallmark of all grades of glioma. To improve tumor localization and prevent unanticipated toxicity, anti-tumor drug delivery mechanisms must be upgraded in parallel with pharmacotherapeutics. Monocytes can easily pass the blood-brain barrier, and thus, drugs with difficulty entering the brain can be loaded into monocytes, resulting in the treatment of brain cancers. RNA as a natural and biocompatible polymer has many advantages for biomedical applications, and RNA-based therapies can provide regulated biological functions by highly selective and controlling means. In this context, macrophages are excellent carriers for distributing RNA-based treatments. However, developing an efficient macrophage-targeted RNA delivery has remained challenging. Several approaches have been introduced in the last decade to efficiently deliver RNA-based therapy via macrophages to treat GBM and inflammatory conditions. This review summarizes the most suitable nano-carrier systems to deliver RNA into immunocytes; also, different methods of synthesizing RNA-loaded nanoparticles and their application, with an emphasis on targeting GBM, are discussed. Furthermore, it focuses specifically on the stability of such nanoformulations and the effect of targeting moieties and adjuvants in determining the worth of the aroused immune response. Finally, the critical aspects of delivering RNA-lipid hybrid nanoparticles (LNPs) via oral, systemic, and local routes are highlighted. We hope that these findings will pave the way for more effective treatment of solid tumors, such as GBM, in the future.