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 NapG^DF^DF^DY 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.