This review article focuses on the physicochemical mechanisms underlying nanoparticle (NP) uptake into cells. It discusses how the kinetics, energetics, and forces are related to interactions between NPs and cell membranes, and how these factors depend on the size, shape, and stiffness of NPs, as well as the biomechanical properties of the cell membrane and the local environment of the cells. The article explores the fundamental principles of NP-cell interactions, which may guide new studies of NP endocytosis and lead to better strategies for designing NP-based approaches in biomedical applications. The review covers various endocytic pathways, including phagocytosis, macropinocytosis, clathrin-mediated endocytosis, caveolin-dependent endocytosis, and non-specific interactions. It also discusses the role of specific and nonspecific interactions in NP-cell membrane interactions, the impact of NP size and shape on endocytic efficiency, and the influence of local mechanical environmental effects. The article provides theoretical foundations and computational models to explain these mechanisms, including coarse-grained models and molecular dynamics simulations.This review article focuses on the physicochemical mechanisms underlying nanoparticle (NP) uptake into cells. It discusses how the kinetics, energetics, and forces are related to interactions between NPs and cell membranes, and how these factors depend on the size, shape, and stiffness of NPs, as well as the biomechanical properties of the cell membrane and the local environment of the cells. The article explores the fundamental principles of NP-cell interactions, which may guide new studies of NP endocytosis and lead to better strategies for designing NP-based approaches in biomedical applications. The review covers various endocytic pathways, including phagocytosis, macropinocytosis, clathrin-mediated endocytosis, caveolin-dependent endocytosis, and non-specific interactions. It also discusses the role of specific and nonspecific interactions in NP-cell membrane interactions, the impact of NP size and shape on endocytic efficiency, and the influence of local mechanical environmental effects. The article provides theoretical foundations and computational models to explain these mechanisms, including coarse-grained models and molecular dynamics simulations.