Ultrasound (US)-driven sonodynamic therapy (SDT) has demonstrated wide application prospects in the eradication of deep-seated bacterial infections due to its noninvasiveness, site-confined irradiation, and high-tissue-penetrating capability. However, the ineffective accumulation of sonosensitizers at the infection site, the hypoxic microenvironment, as well as rapid depletion of oxygen during SDT greatly hamper the therapeutic efficacy of SDT. Herein, an US-switchable nanozyme system was proposed for the controllable generation of catalytic oxygen and sonosensitizer-mediated reactive oxygen species during ultrasound activation, thereby alleviating the hypoxia-associated barrier and augmenting SDT efficacy. This nanoplatform (Pd@Pt-T790) was easily prepared by bridging enzyme-catalytic Pd@Pt nanoplates with the organic sonosensitizer meso-tetra­(4-carboxyphenyl)­porphine (T790). It was really interesting to find that the modification of T790 onto Pd@Pt could significantly block the catalase-like activity of Pd@Pt, whereas upon US irradiation, the nanozyme activity was effectively recovered to catalyze the decomposition of endogenous H2O2 into O2. Such “blocking and activating” enzyme activity was particularly important for decreasing the potential toxicity and side effects of nanozymes on normal tissues and has potential to realize active, controllable, and disease-loci-specific nanozyme catalytic behavior. Taking advantage of this US-switchable enzyme activity, outstanding accumulation in infection sites, as well as excellent biocompatibility, the Pd@Pt-T790-based SDT nanosystem was successfully applied to eradicate methicillin-resistant Staphylococcus aureus (MRSA)-induced myositis, and the sonodynamic therapeutic progression was noninvasively monitored by photoacoustic imaging and magnetic resonance imaging. The developed US-switchable nanoenzyme system provides a promising strategy for augmenting sonodynamic eradication of deep-seated bacterial infection actively, controllably, and precisely.

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Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O2 for cancer starvation therapy, while the O2 produced from the decomposition of endogenous H2O2 by the Pd@Pt with the CAT-like activity could accelerate the O2-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H2O2 content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H2O2 to generate abundant highly toxic •OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.