<p>Bacterial infection poses a significant challenge in clinical wound management. Traditional antibiotic therapies are hampered by cytotoxicity and the emergence of drug resistance. However, current photodynamic therapy (PDT) and nanozyme-based antibacterial strategies often lack microenvironment specificity, exhibiting persistent activity that risks tissue damage. To overcome these limitations, we developed bacterial microenvironment responsive Fe-Ce6 nanoparticles (NPs) for <i>in situ</i> generation of peroxidase (POD)-like activity and PDT activation to enhance antibacterial wound therapy. Under bacteria-secreted ATP stimulation, Fe-Ce6 NPs disassembled and <i>in situ</i> formed Fe-ATP complexes, while synchronously releasing the Ce6 photosensitizer. The Fe-ATP complex with POD like activity converts H₂O₂ into hydroxyl radicals (·OH), and Ce6 generates singlet oxygen (¹O₂) under 671 nm laser irradiation, synergistically enhancing nanozyme-PDT antibacterial effects. The intracellular ATP released from lysed bacteria further amplifies this cascade, promoting the formation of Fe-ATP complex and the release of Ce6, ultimately inducing an “avalanche effect”, efficiently killing bacteria and reinforcing therapeutic action. <i>In vitro</i>, the system demonstrates remarkable antibacterial activity against <i>S. aureus</i> and <i>E. coli</i> in simulated bacterial environments. <i>In vivo</i>, it exhibits substantial bactericidal efficacy and accelerates wound healing. This study presents the Fe-Ce6 NPs smart system activated by bacterial microenvironments via an “off-on” mechanism, enabling precise reactive oxygen species generation control, significantly reducing non-target tissue damage associated with traditional therapies, and offering a novel paradigm for developing microenvironment-responsive intelligent antibacterial systems.</p>