Anne Bernheim

Efficient transport to the nuclear envelope is a prerequisite for many nucleus-targeted drug delivery strategies. We develop an enhanced, energy-based simulation of spherical nanoparticle (NP) complexes hauled by multiple dynein motors via flexible polymer linkers, aimed at deriving design rules for nucleus-directed delivery. The model extends prior work by treating dynein as a semi-flexible polymer and enforcing path-wise steric exclusion along full stepping trajectories. Event propensities follow a Monte-Carlo scheme with energies that couple linker entropy, dynein bending, and binding enthalpy; post-event mechanical relaxation uses gradient descent. We compare our model results to recent motility assays of spherical NPs decorated with polyethylene-glycol (PEG) polymers, each ending with a nuclear-localisation-signal (NLS) peptide that can recruit dynein from the cytoplasm. With standardised biophysical parameters, the model captures the observed dependence on motor number: longitudinal velocity decreases with dynein load, whereas run-distance and run-time increase. For mean NP-bound motors between 1 and 6, the model results lie within the experimental 95% confidence intervals. A systematic scan of polymer contour length, for a 20 nm radius cargo hauled by six motors, reveals a clear optimum of the run-time and run-length at about 40 nm length, despite a reduction in velocity. Similar results, for different cargo sizes and motor loading, can be obtained using our model-based computer code. They can provide a quantitative basis for tuning linker contour length (and, secondarily, motor loading by tuning PEG-NLS density) when engineering NP vehicles that exploit native microtubule transport for nucleus-directed delivery.