Unravel the Tangle: Atomistic Insight into Ultrahigh Curcumin‐Loaded Polymer Micelles

Abstract Amphiphilic ABA‐triblock copolymers, comprised of poly(2‐oxazoline) and poly(2‐oxazine), can solubilize poorly water‐soluble molecules in a structure‐dependent manner forming micelles with exceptionally high drug loading. All‐atom molecular dynamics simulations are conducted on previously experimentally characterized, curcumin‐loaded micelles to dissect the structure‐property relationships. Polymer–drug interactions for different levels of drug loading and variation in polymer structures of both the inner hydrophobic core and outer hydrophilic shell are investigated. In silico, the system with the highest experimental loading capacity shows the highest number of drug molecules encapsulated by the core. Furthermore, in systems with lower loading capacity outer A blocks show a greater extent of entanglement with the inner B blocks. Hydrogen bond analyses corroborate previous hypotheses: poly(2‐butyl‐2‐oxazoline) B blocks, found experimentally to have reduced loading capacity for curcumin compared to poly(2‐propyl‐2‐oxazine), establish fewer but longer‐lasting hydrogen bonds. This possibly results from different sidechain conformations around the hydrophobic cargo, which is investigated by unsupervised machine learning to cluster monomers in smaller model systems mimicking different micelle compartments. Exchanging poly(2‐methyl‐2‐oxazoline) with poly(2‐ethyl‐2‐oxazoline) leads to increased drug interactions and reduced corona hydration; this suggests an impairment of micelle solubility or colloidal stability. These observations can help driving forward a more rational a priori nanoformulation design.