This review discusses the physiochemical mechanisms underlying nanoparticle (NP) uptake into cells. When NPs approach a cell, interactions with the cell membrane generate forces that lead to membrane wrapping and cellular uptake. The article explores how kinetics, energetics, and forces relate to these interactions, influenced by NP size, shape, stiffness, cell membrane properties, and local environment. It provides a theoretical foundation for understanding NP entry via endocytosis, distinguishing it from previous reviews that focused on experimental observations or computational simulations. The review also extends previous studies on cell-NP interactions and vesicle wrapping. The article discusses various endocytic pathways, including phagocytosis, macropinocytosis, and clathrin- and caveolin-mediated endocytosis. It highlights the role of mechanical forces, adhesion, and ligand-receptor binding in NP uptake. The review also addresses the size effect on NP endocytosis, showing that smaller NPs may enter cells through translocation or membrane curvature-mediated aggregation. It analyzes the kinetics of NP endocytosis, showing that the time required depends on receptor diffusion and ligand density. The optimal NP size for minimal endocytic time is around 27–30 nm. The review also discusses the optimal conditions for cellular uptake, showing that the number of NPs a cell can take up depends on NP size, ligand density, and receptor availability. It identifies an optimal NP size and ligand density for maximizing cellular uptake. The review further explores the shape effect, noting that nonspherical NPs exhibit unique wrapping modes during endocytosis. It also discusses coarse-grained models for simulating NP endocytosis, highlighting their computational efficiency and ability to capture biophysical interactions. The review also addresses the uptake of 1D and 2D nanomaterials, showing that their interaction with cell membranes depends on membrane tension and the geometry of the nanomaterial. It discusses the uptake of soft NPs, where both the cell membrane and NP deform, affecting the energy landscape and endocytosis kinetics. The review concludes that understanding the physiochemical principles of NP-cell interactions is crucial for designing effective NP-based biomedical applications.This review discusses the physiochemical mechanisms underlying nanoparticle (NP) uptake into cells. When NPs approach a cell, interactions with the cell membrane generate forces that lead to membrane wrapping and cellular uptake. The article explores how kinetics, energetics, and forces relate to these interactions, influenced by NP size, shape, stiffness, cell membrane properties, and local environment. It provides a theoretical foundation for understanding NP entry via endocytosis, distinguishing it from previous reviews that focused on experimental observations or computational simulations. The review also extends previous studies on cell-NP interactions and vesicle wrapping. The article discusses various endocytic pathways, including phagocytosis, macropinocytosis, and clathrin- and caveolin-mediated endocytosis. It highlights the role of mechanical forces, adhesion, and ligand-receptor binding in NP uptake. The review also addresses the size effect on NP endocytosis, showing that smaller NPs may enter cells through translocation or membrane curvature-mediated aggregation. It analyzes the kinetics of NP endocytosis, showing that the time required depends on receptor diffusion and ligand density. The optimal NP size for minimal endocytic time is around 27–30 nm. The review also discusses the optimal conditions for cellular uptake, showing that the number of NPs a cell can take up depends on NP size, ligand density, and receptor availability. It identifies an optimal NP size and ligand density for maximizing cellular uptake. The review further explores the shape effect, noting that nonspherical NPs exhibit unique wrapping modes during endocytosis. It also discusses coarse-grained models for simulating NP endocytosis, highlighting their computational efficiency and ability to capture biophysical interactions. The review also addresses the uptake of 1D and 2D nanomaterials, showing that their interaction with cell membranes depends on membrane tension and the geometry of the nanomaterial. It discusses the uptake of soft NPs, where both the cell membrane and NP deform, affecting the energy landscape and endocytosis kinetics. The review concludes that understanding the physiochemical principles of NP-cell interactions is crucial for designing effective NP-based biomedical applications.