Nothing gets a difficult job done better than great teamwork. In the human body, enzymes work together to facilitate tightly coordinated chain reactions, operating like catalytic tag teams. Molecular products are passed from one enzyme to the next in these cascades, resulting in complex biochemical processes that are essential for cell and organ function.
New therapeutic strategies inspired by these enzymatic cascades aim to restore biochemical balance in metabolically stressed environments, such as post-surgical wounds. After pancreatic surgery, for instance, skin wounds are often burdened by damaging reactive oxygen species (ROS), limited oxygen supply and high glucose levels that can nourish infection-causing bacteria.
Researchers like Xiaotong Fan, a Scientist at the A*STAR Institute of Sustainability for Chemicals, Energy and Environment (A*STAR ISCE2), are hoping multi-enzyme therapies can help accelerate wound healing and tissue repair. “Earlier multi-enzyme delivery platforms have often suffered from enzyme leakage, limited stability and low reaction efficiency,” said Fan.
To address these design gaps, Fan, along with Senior Principal Scientist Chaobin He from the A*STAR Institute of Materials Research and Engineering (A*STAR IMRE) and Director of the Resource Circularity Division Zibiao Li of A*STAR IMRE and A*STAR ISCE2, collaborated with researchers from National University of Singapore; and Fuzhou University and Fujian Provincial Hospital in China.
Together, they assembled a three-enzyme rescue team: glucose oxidase (GOX), superoxide dismutase (SOD) and catalase (CAT). Each enzyme was first encased in a thin polymer network to protect against harsh environments that could compromise reactivity. Acting as molecular glue, zinc ions then clustered the enzymes together, forming a zinc-coordinated tri-enzyme nanogel system (Zn@nGSC).
“This design not only prevents enzyme leakage but also ensures spatial confinement of the enzymes, thereby significantly enhancing cascade reaction efficiency,” explained He.
The team tested their system in a mouse model with skin wounds following partial pancreatic surgery. In Zn@nGSC’s choreographed reaction sequence, GOX consumes excess glucose and further sets off processes to prevent infection. SOD and CAT work together to neutralise ROS to drive down inflammation and to oxygenate tissues, accelerating skin repair.
Zn@nGSC-treated animals showed faster wound closure, reduced bacterial infections, and improved blood vessel formation. Crucially, the tri-enzyme system remained stable under physiological conditions and outperformed platforms carrying only one or two enzymes.
“Our results demonstrate that biological complexity cannot be effectively addressed by isolated enzymatic functions,” said Fan. “Instead, multi-enzyme systems like Zn@nGSC can reprogram disease microenvironments in a more integrated and holistic way.”
To improve their tri-enzyme strategy, the researchers plan to adapt the system to other metabolically compromised environments beyond skin wounds. They also hope to improve the system’s responsiveness to dynamically meet the evolving demands of diseased tissues.
“Our next goal is to enable precise activation of enzymes only when and where they are needed, so that local biochemical balance can be restored in a controlled and efficient manner,” said Li.
The A*STAR-affiliated researchers contributing to this research are from A*STAR Institute of Sustainability for Chemicals, Energy and Environment (A*STAR ISCE2) and A*STAR Institute of Materials Research and Engineering (A*STAR IMRE).
