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

Abstract

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.