Exploring the internalization pathways of silica nanoparticles for targeted intracellular delivery: a discussion of recent results

The advances in nanotechnology and nanomedicine have enabled the development of minimally invasive, high-performance drug delivery systems with enhanced targeting and therapeutic abilities. In this context, the high biocompatibility, tunable surface chemistry and physicochemical properties of SiO₂ nanoparticles (SNPs), have placed them as key representatives in this field. However, the clinical success of SNP-based systems highly depends on the mechanism involved in their internalization process, which further determines their intracellular fate and therapeutic function. Considering the importance of this aspect, this review critically addresses the most relevant and recent studies focused on the in vitro cellular uptake mechanisms of SNPs, published in the last 5 years. After a concise introduction of the SNPs' properties, as well as the main cell internalization mechanisms, representative studies are discussed. For a better overview, the discussion is divided into two main sections. While the first part presents the SNP interaction in single-cell culture models, offering insights into the precise behaviour of certain cell types (immune cells - RAW 264.7 macrophage-like cells and specialized cells - epithelial cells, endothelial cells, osteoblasts, cancer cells and stem cells), the second section compares the uptake dynamics across multiple cell lines (epithelial cells and cancer cells, bone cancer cells, glioblastoma and osteoblasts; endothelial, fibroblasts, cancer cells and macrophage-like cells, etc.). The current limitations and emerging perspectives for translating these concepts into medical practice are finally briefly addressed.