Predictive Amphiphile Design Enables Control of Self-Assembled Nanoparticle-Cell Membrane Interactions.
Despite decades of development, the clinical translation of amphiphilic self-assembled nanoparticles remains limited by the lack of a predictive molecular design framework, owing to the complex, dynamic behavior of nanoparticles and cell membranes. Here, we introduce a building-block design strategy focused on amphiphile monomers rather than assembled nanoparticles, a critical distinction because nanoparticle morphology is not a fixed design parameter. This molecular framework links amphiphile chemical structure to programmable cellular interactions. Through predictive variation of headgroup and tail chemistries, we demonstrate that amphiphile design dictates nanoparticle fate at cell membranes. Fully fluorinated nanoparticles remain intact and adsorb onto the membrane surface, hydrocarbon nanoparticles rapidly dissociate and fuse, whereas semi-fluorinated nanoparticles exhibit tunable kinetic delays, enabling programmable responses such as stability at rigid interfaces but dissociation at fluid membranes. Crucially, we identify the free energy of transfer (ΔGtransfer)-the energetic difference between extracting an amphiphile from the nanoparticle and from the cell membrane-as a unified thermodynamic descriptor that accurately predicts behavior across simulations and experiments without requiring full-system modeling. Collectively, this predictive, chemistry-driven framework shifts the design paradigm from nanoparticle morphology to amphiphile chemistry, enabling the rational engineering of self-assembled nanocarriers for targeted drug delivery and responsive drug release applications.