Physical mechanisms of nanoparticle intracellular release through membrane pore nucleation and expansion

Successful intracellular delivery requires a nanocarrier to adhere to the cell membrane, be wrapped and internalized and finally released into the cytoplasm before it is degraded. While the initial steps have been intensively studied, the intracellular release of a nanocarrier has received comparatively less attention and remains poorly understood. To understand the physical mechanisms that govern intracellular release, we investigate the escape of nanocarriers (radii 4.5{sigma} and 7{sigma} ) from a lipid vesicle using coarse-grained simulations. We represent a nanocarrier using the metaparticle model and the membrane using the three-beads Cooke-Deserno model. Starting from a fully endocytosed state, we systematically vary the repulsion between the nanoparticle and the lipid head groups and compare three release scenarios: passive release, localized inside-out activity from a drug-like source confined within the particle and activity distributed over the entire nanoparticle. An elastic-energy analysis shows that in a tensionless membrane escape requires crossing a large pore-expansion barrier of {approx} 68kBT for the smaller particle and {approx} 110kBT for the larger, making passive release thermodynamically improbable. Our results show that the smaller particle nonetheless escapes above a threshold repulsion, whereas the larger one remains trapped in a metastable state in which local membrane pores form but fail to grow beyond the particle diameter to allow successful release. Adding activity lowers the nucleation barrier and promotes earlier pore opening, but its effectiveness depends on how it is applied, i.e., a localized internal source assists release of the smaller particle yet is insufficient to systematically free the larger one, while activity distributed across the whole nanoparticle drives complete release even in the larger case. These results show that productive escape is governed by whether the resulting pore can evolve into a geometrically accessible release pathway, providing physical design principles for intracellular delivery by nanocarriers