Poly(2-isopropenyl-2-oxazoline) hydrogels as multipurpose drug delivery systems: Tailoring molecular interactions for controlled loading and release

• PiPOx hydrogels enable delivery of diverse therapeutic drug classes. • pH-responsive loading and release achieved via 2-oxazoline protonation. • Crosslinker chemistry fine tunes hydrogel drug release rates. Poly(2-isopropenyl-2-oxazoline) (PiPOx) is an established polymer used in the synthesis of a wide range of functional materials with tailored properties designed to meet the demands of specific applications, particularly in the biomedical field. In the present study, we report on the therapeutic potential of PiPOx hydrogels systems by evaluating their drug loading capacity and drug release kinetics using pharmacologically active compounds belonging to diverse therapeutic classes. The exceptional versatility of PiPOx hydrogels as a drug delivery platform arises from their ability to engage in a diverse array of non-covalent interactions such as ionic, cation-π, ion–dipole, hydrophobic, and hydrogen bonding that can be established between the 2-oxazoline rings, crosslinks, and the drugs. Moreover, the weakly basic nature of the 2-oxazoline units allows protonation, enabling pH-responsive control over drug loading and drug release, while the chemical nature of the crosslinker allows further fine-tuning of the release profile through secondary physical interactions with the drug, resulting in sustained drug release profiles. Finally, the identified structure–property relationships enabled the rational use of PiPOx hydrogels as RNA delivery platforms.