Hydroxyurea-coordinated copper-based metal-organic framework nanoreactor for glucose-gated nitric oxide release and...

Nitric oxide (NO)-based therapy represents a promising strategy against multidrug-resistant infections owing to its broad-spectrum antibacterial activity and minimal propensity to induce resistance. Hydroxyurea (HyU), a clinically approved drug for sickle cell disease, has recently emerged as a hydrogen peroxide (H₂O₂)-responsive NO precursor. However, the hydroxamic acid moiety responsible for NO generation is highly susceptible to hydrolytic degradation in aqueous environments, severely limiting its therapeutic utility. Herein, we report a coordination-driven stabilization strategy that incorporates HyU as a coordinating component within a Cu(II)-based metal-organic framework (CuPH). Coordination with Cu(II) preserves the chemical integrity of HyU for at least 14 days under physiological conditions, enabling its use as a stable NO precursor within a glucose-responsive nanoreactor. Using this stabilized framework, glucose oxidase (GOx) is co-confined within CuPH to construct a nanoreactor (GOx@CuPHcs). Under hyperglycemic wound conditions, GOx catalyzes in situ H₂O₂ generation from glucose, which subsequently activates Cu-mediated oxidation of coordinated HyU to achieve glucose-gated and on-demand NO release. The generated NO effectively eliminates methicillin-resistant Staphylococcus aureus (MRSA) and disrupts mature biofilms. GOx@CuPHcs was also associated with macrophage phenotype remodeling, enhanced fibroblast migration, and accelerated wound healing in a diabetic murine model with negligible systemic toxicity. This work demonstrates that coordination interactions can improve the stability of hydrolytically labile therapeutic molecules while enabling their integration into stimulus-responsive nanoreactors, highlighting the potential of coordination-based strategies for developing advanced therapeutic systems.