Hyperglycemia-driven pH-gated multi-enzyme cascade nanoparticle microneedles for programmed therapy of diabetic infected wounds

Chronic diabetic wounds heal poorly due to persistent hyperglycemia, recurrent infection, and dysregulated inflammation, while their complex microenvironment poses major therapeutic challenges. Yet, therapeutic strategies that actively modulate the wound microenvironment for microenvironment-responsive treatment remain largely underexplored. Here, we engineered a biomimetic multi-enzyme nanozyme and integrated it into an adaptive PBEG@GelMA hydrogel microneedle system to convert excessive glucose into an endogenous substrate for antibacterial therapy. This system establishes a glucose-responsive and pH-dependent catalytic strategy featuring coordinated POD-, CAT-, and SOD-like activities, enabling integrated regulation of glucose levels, bacterial infection, oxidative stress, and wound microenvironment. Mechanistically, (i) glucose oxidase (GOx) senses hyperglycemia, consumes glucose, and generates gluconic acid and H 2 O 2 , depriving bacteria of nutrients while priming POD-like catalysis; (ii) under acidic conditions, dissociation of GOx exposes positively charged PB@EPL, which binds to negatively charged bacterial surfaces and enhances POD-like activity to convert H 2 O 2 into highly reactive ·OH, efficiently eliminating bacteria and biofilms with a bactericidal rate above 99.56%; and (iii) after infection control and pH normalization, SOD- and CAT-like activities remove excess O 2 ·− and H 2 O 2 while generating oxygen to relieve hypoxia and inflammation. This microenvironment-responsive cascade supports antibacterial treatment and subsequent tissue regeneration, promoting angiogenesis, collagen deposition, and metabolic homeostasis, thereby breaking the hyperglycemia-infection-inflammation vicious cycle. An intelligent PBEG@GelMA microneedle platform, endowed with environmental responsiveness, enzyme cascade reactions, and photothermal enhancement, enables glucose regulation, antibacterial and anti-inflammatory therapy, thereby achieving deep-tissue intervention.