From triggers to interfaces: polymer-stabilized nano-co-crystals for robust mesalazine delivery in UC

Ulcerative colitis profoundly alters the colonic environment, challenging conventional oral drug delivery. Fluctuating luminal pH, irregular transit, mucus remodelling, oxidative stress and microbiota dysbiosis can destabilise trigger-dependent mesalazine formulations and contribute to inconsistent colonic drug exposure.

This review examines the mechanistic limitations of trigger-dependent mesalazine delivery and evaluates whether increasing formulation complexity through multi-responsive systems provides sufficient benefit under the heterogeneous and unstable conditions of active ulcerative colitis.

The review analyses how pathological changes in the colonic environment influence pH-, enzyme- and inflammation-responsive systems and considers polymer-stabilised nano-co-crystal interfacial engineering as a trigger-independent approach. Particular attention is given to crystal engineering and polymer-mediated regulation at the solid-liquid and drug-mucus interfaces.

Trigger-dependent systems rely on pathological cues that vary spatially and temporally during active disease, which can produce variable drug release and colonic exposure. Polymer stabilisation of nano-co-crystals provides an alternative means of controlling drug performance at the formulation interface. Polymer adsorption onto high-energy nano-co-crystal surfaces can stabilise crystalline domains, moderate dissolution, suppress aggregation and recrystallisation, and maintain controlled supersaturation under changing colonic conditions. Polymer functionality may also improve interaction with inflammation-modified mucus, prolong mucosal residence and reduce luminal washout.

Using mesalazine as a representative drug, this review reframes colonic delivery in ulcerative colitis as an interface-dominated problem. Polymer-stabilised nano-co-crystals offer a trigger-independent strategy in which drug performance is regulated through crystal and polymer interfaces rather than fluctuating luminal conditions, providing a rational basis for further development of disease-adaptive colonic delivery systems.