Despite the increasing use of nanoparticles (NPs), our current knowledge of how NPs interact with the human body or the environment remains limited. Of a number of mechanisms, a direct route via which NPs can mediate toxicity is to invade cells by crossing the cell membrane. Thus, understanding this NP-membrane-crossing process, and how it is affected by NPs¿ physical properties such as size, shape and surface chemistry, is central to our fundamental understanding of nanotoxicity. Previous clinical and biomedical studies have focused on phenomenological observations: i.e., NPs either invade cells or they don¿t; cells consequently either die or they don¿t. Studies, theoretical or experimental, addressing the fundamental mechanisms involved are very few. Here, the central fundamental question we would like to ask is: How would the presence of NPs modify the energetics of membrane fusion?