Zinc-Coordinated Trienzyme Nanogel Cascade Therapy for Accelerated Post-Pancreatectomy Cutaneous Wound Healing.

Orchestration of enzyme cascades in synthetic systems remains a major challenge for catalytic control in complex biological environments. Here, a zinc-coordinated tri-enzyme nanogel system (Zn@nGSC) is reported that mimics natural enzymatic assemblies by confining individual glucose oxidase (GOX), superoxide dismutase (SOD), and catalase (CAT) within an imidazole-functionalized polymeric nanogel matrix. The nanogel is fabricated via mild in situ polymerization combined with Zn2⁺-imidazole coordination, yielding structurally stable multi-enzyme assemblies. The engineered assemblies demonstrate simultaneous preservation of enzymatic activity and enhanced cascade efficiency under thermal and proteolytic stress. Cascade reactions proceed as follows: i) glucose is depleted by GOX, ii) superoxide radicals are scavenged by SOD to alleviate oxidative stress, and iii) residual H2O2 is converted into oxygen by CAT in order to mitigate hypoxia. Functionally, Zn@nGSC restores redox balance and metabolic homeostasis, demonstrated in a murine model of post-pancreatectomy wound healing, with emphasis on treating hyperglycemia and improving regeneration. Another pronounced advantage of Zn@nGSC treatment is its antibacterial effect, which enhances angiogenesis, collagen deposition, and immune modulation. Overall, this modular nanoplatform provides a blueprint for designing robust, bioresponsive cascade systems with therapeutic potential in metabolically compromised microenvironments.