Multi-enzyme cascade reactions play a fundamental role in biosynthesis, energy metabolism, cell signaling, proliferation, and cell death in living cells. These reactions have been proposed as a strategy to treat cancer by overproducing reactive oxygen species, depleting nutrients in tumors, or remodeling the immunosuppressive microenvironment. However, the co-delivery of multiple enzymes with optimal cascade catalytic activity remains challenging. Here, we present polymer nanoparticles loaded with glucose oxidase (GOx), lactate oxidase (LOx), and chloroperoxidase (CPO).Used for synergistic cancer catalytic therapy. These enzymes complex with ε-polylysine modified with nitrobenzyl groups through ionic and hydrophobic interactions, and then undergo photoactivated crosslinking to prepare serum-stable and pH-responsive protein nanoparticles. The GOx and LOx in the nanoparticles effectively consume glucose and lactate, generating excess hydrogen peroxide, while CPO further catalyzes hydrogen peroxide to produce singlet oxygen (1O2) in the presence of chloride ions.Promotes apoptosis and ferroptosis of cancer cells. Triple-enzyme polymer nanoparticles effectively inhibit tumor growth in osteosarcoma models without causing significant adverse effects. This multi-enzyme delivery system provides a promising tool for treating diseases through multi-enzyme cascade reactions.

Original link

A polymeric triple-enzyme nanoparticle by light activatable crosslinking for cascade catalytic therapy of osteosarcoma

Pub Date : 2025-11-08

DOI: 10.1016/j.bioactmat.2025.10.042

Lanfang Ren,  Xin Yu,  Chunyang Yuan,  Fang Zhu,  Haohan Zhou,  Qianqian Chen,  Jia Lv,  Zhoufang Mei,  Yiyun Cheng,  Zhengwang Sun