D-peptide engineered hydrogel with dual-enzyme-ALA cascades enables multimodal oxygen modulation for self-sustaining EDT-PDT synergy.

The transformation of O2 is primarily facilitated by the catalytic action of redox enzymes, which play a pivotal role in sustaining cellular energy metabolism and redox balance. Bioinspired by O2 distribution and ROS regulation related to cascade biocatalytic process, a D-peptide NapGDFDFDY engineered hydrogel has been constructed with encapsulated dual-enzyme superoxide (SOD) and chloroperoxidase (CPO) cascade catalytic circuit and co-assembled photosensitizer of 5-aminolevulinic acid molecules (ALA). Multimodal oxygen modulation has been conducted by the concurrent oxygen generation via SOD-catalyzed ⋅O2 - dismutation and oxygen consumption for 1O2 production by CPO and ALA, achieving self-sustaining enzymatic dynamic therapy (EDT)-photodynamic therapy (PDT) (EDT-PDT) synergy. The endogenous cascade-amplified EDT not only enhances the 1O2 efficacy in exogenous PDT therapy, but the intermediate O2 can also alleviate local neuropathic pain caused by hypoxia for safe PDT treatment. This work pioneers enzyme-mediated dynamic control of tumor redox homeostasis, establishing a new therapeutic axis between biocatalytic amplification and photodynamic processes.