Think Beyond The Core: Computationally Decoding the Hydrophilic Corona of Drug-Loaded Polymer Micelles

Polymeric micelles are established delivery platforms for hydrophobic drugs. The molecular interactions governing their structure and function remain, however, poorly understood. All-atom molecular dynamics simulations are used to investigate drug-loaded ABA-type triblock copolymer micelles with a hydrophobic poly(2-n-butyl-2-oxazine) core and hydrophilic coronas composed of poly(ethylene glycol) (pEG), poly(N,N-dimethylacrylamide) (pDMAA), and poly(sarcosine) (pSAR). Here, pDMAA and pSAR are considered as alternative polymers to address emerging pEG immunogenicity. Three micellar formulations are examined at moderate (20%) and high (60%) loadings of curcumin as a model hydrophobic drug. The simulations reveal that pEG-based micelles exhibit higher hydration and looser corona structures compared to pDMAA and pSAR micelles. In pEG micelles, curcumin localizes primarily within the hydrophobic core, whereas in pDMAA and pSAR micelles it is more uniformly distributed. At both drug loadings, curcumin preferentially aggregates into a single stable cluster, not densely packed, and interpenetrated by polymer chains. Micelles with pDMAA and pSAR coronas exhibit enhanced stability, reflecting higher internal density and tighter curcumin packing. Hydrogen bond analysis reveals the strongest curcumin-hydrophilic A-block interactions in pDMAA micelles, moderate loading-dependent interactions in pSAR micelles, and minimal hydrogen-bonding in pEG micelles due to corona hydration.