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

The transformation of O 2 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 O 2 distribution and ROS regulation related to cascade biocatalytic process, a D-peptide NapG D F D F D Y 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 ⋅O 2 − dismutation and oxygen consumption for 1 O 2 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 1 O 2 efficacy in exogenous PDT therapy, but the intermediate O 2 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. • D-peptide hydrogel was constructed with dual-enzyme cascade catalytic circuit and co-assembled 5-aminolevulinic acid (ALA). • Multimodal oxygen modulation was conducted by SOD induced O 2 − dismutation and O 2 generation for 1 O 2 production by CPO /ALA. • Self-sustaining enzymatic dynamic therapy (EDT)-photodynamic therapy (PDT) synergy was achieved. • The endogenous EDT enhances the 1 O 2 efficacy in exogenous PDT, the intermediate O 2 also alleviates local neuropathic pain.