Biofilm microenvironment (BME)-activated antimicrobial agents display great potential for improved biofilm-related infection therapy because of their superior specificities and sensitivities, effective eliminations, and minimal side effects. Herein, BME-activated Fe-doped polydiaminopyridine nanofusiform-mediated single-atom nanozyme (FePN SAzyme) is presented for photothermal/chemodynamic synergetic bacteria-infected wound therapy. The photothermal therapy (PTT) function of SAzyme can be specifically initiated by the high level of H 2 O 2 and further accelerated through mild acid within the inflammatory environment through "two-step rocket launching-like" process. Additionally, the enhanced chemodynamic therapy (CDT) for the FePN SAzyme can also be endowed by producing hydroxyl radicals through reacting with H 2 O 2 and consuming glutathione (GSH) of the BME, thereby contributing to more efficient synergistic therapeutic effect. Meanwhile, FePN SAzyme could catalyze biofilm-overexpressed H 2 O 2 decomposing into O 2 and overcome the hypoxia of biofilm, which significantly enhances the susceptibility of biofilm and increases the synergistic efficacy. Most importantly, the synergistic therapy of bacterial-induced infection diseases can be switched on by the internal and external stimuli simultaneously, resulting in minimal nonspecific damage to healthy tissue. These remarkable characteristics of FePN SAzyme not only develop an innovative strategy for the BME-activated combination therapy but also open a new avenue to explore other nanozyme-involved nanoplatforms for bacterial biofilm infections.

Nanozyme-based tumor collaborative catalytic therapy has attracted a great deal of attention in recent years. However, their cooperative outcome remains a great challenge due to the unique characteristics of tumor microenvironment (TME), such as insufficient endogenous hydrogen peroxide (H 2 O 2 ) level, hypoxia, and overexpressed intracellular glutathione (GSH). Methods: Herein, a TME-activated atomic-level engineered PtN 4 C single-atom nanozyme (PtN 4 C-SAzyme) is fabricated to induce the “butterfly effect” of reactive oxygen species (ROS) through facilitating intracellular H 2 O 2 cycle accumulation and GSH deprivation as well as X-ray deposition for ROS-involving CDT and O 2 -dependent chemoradiotherapy. Results: In the paradigm, the SAzyme could boost substantial ∙OH generation by their admirable peroxidase-like activity as well as X-ray deposition capacity. Simultaneously, O 2 self-sufficiency, GSH elimination and elevated Pt 2+ release can be achieved through the self-cyclic valence alteration of Pt (IV) and Pt (II) for alleviating tumor hypoxia, overwhelming the anti-oxidation defense effect and overcoming drug-resistance. More importantly, the PtN 4 C-SAzyme could also convert O 2 ·- into H 2 O 2 by their superior superoxide dismutase-like activity and achieve the sustainable replenishment of endogenous H 2 O 2 , and H 2 O 2 can further react with the PtN 4 C-SAzyme for realizing the cyclic accumulation of ∙OH and O 2 at tumor site, thereby generating a “key” to unlock the multi enzymes-like properties of SAzymes for tumor-specific self-reinforcing CDT and chemoradiotherapy. Conclusions: This work not only provides a promising TME-activated SAzyme-based paradigm with H 2 O 2 self-supplement and O 2 -evolving capacity for intensive CDT and chemoradiotherapy but also opens new horizons for the construction and tumor catalytic therapy of other SAzymes.

No abstract