Nanoparticles are promising drug carriers for targeted therapies, diagnostic imaging, and advanced vaccines. However, their clinical translation is limited by complex biological barriers that reduce cellular uptake and efficacy. In particular, the interaction with the cellular membrane controls nanoparticle adhesion, wrapping, or full engulfment, which ultimately governs nanoparticle internalization efficiency. Flexible nanocarriers (e.g., liposomes, polymeric nanogels, and micelles) are particularly attractive because their deformability could help them enhance the probability of successful cellular entry. To understand the physical mechanisms associated with cellular uptake, we investigate the interaction of semi-flexible nanocarriers with a symmetric lipid bilayer using coarse-grained simulations. We represent a flexible nanoparticle using the previously introduced metaparticle model and the membrane using the Cooke–Deserno model. By systematically varying nanoparticle properties, i.e., adhesion strength and topology, we identify distinct interaction regimes ranging from surface adhesion and trapping to complete wrapping and endocytosis. These regimes correlate with nanoparticle shape, size, and surface properties, providing quantitative design principles for optimizing cellular uptake. Overall, this framework offers predictive insight into how the interplay between nanoparticle properties and membrane interaction governs cellular internalization, informing the rational design of next-generation soft nanocarriers and smart materials.
Paesani et al. (2026) studied this question.