The schematic workflow of the modeled systems is shown in Figure . To model the starting structures of the micelles based on the structural insights given from previous experimental work, polymers of the desired lengths were first built in a stretched-out conformation using tleap from AmberTools22. Each polymer chain was then initially relaxed by performing an energy minimization (maximum of 2000 cycles) followed by a short 600 ps-long simulation in Generalized Born implicit solvent 35 (12 Å distance cutoff) using sander from AmberTools22. For each micelle, 35 polymers were then inserted in a loosely spherical orientation using packmol 18.169 (similar to other recent micelle modeling studies ), leaving approximately 33 % of the core volume empty for solvation, assuming a placement of ~50 % of the CUR molecules in this area (the exact number of polymers constituting each micelle was not known a priori from experiments). After placement of the polymers with hydrophilic A blocks oriented towards the outside and hydrophobic B blocks towards the inside, the desired amount of CUR molecules for a [10/2] or [10/6] polymer/drug w/w ratio was inserted randomly within a sphere that spanned the volume of the hydrophobic core as well as parts of the hydrophilic corona. Details of the chosen packmol settings for this pre-assembly of polymers and drugs can be found in the Supporting Information (Figure ). For each micelle, the best solution found by packmol after 50 optimization loops was then solvated in a cubic box with TIP3P water, with a minimum polymer-to-border distance of 10 Å. Chloride ions were used for subsequent neutralization. Structures and topologies were then converted to GROMACS files using ParmEd from AmberTools22. For additional sampling data on polymer-drug interactions while limiting the computational costs, we artificially separated the environment of the hydrophilic corona and the hydrophobic core. To do so, small cubic simulation boxes (~ 5 nm box length) filled with randomly placed shorter hexamer variants of pMeOx / pEtOx / pPrOzi / pBuOx (capped with methyl groups), in addition to CUR and water molecules were created via packmol, in accordance with the respective polymer, drug and water atom densities found after 1.75 µs within the area of the corona and the micelle core of the first replicas (treating polymer densities as one type, either A or B blocks). Hence, for these model systems atom numbers were scaled down to a volume of 125 nm³ from the simulations of the entire micelles. Core densities were taken as an average across the volume up to 2 nm from the micelle center, whereas shell densities were taken from the distribution between 4 and 5 nm from the respective center.