Bioorthogonal catalysis offers a unique strategy to modulate biological processes through the in situ generation of therapeutic agents. However, the direct application of bioorthogonal transition metal catalysts (TMCs) in complex media poses numerous challenges due to issues of limited biocompatibility, poor water solubility, and catalyst deactivation in biological environments. We report here the creation of catalytic "polyzymes", comprised of self-assembled polymer nanoparticles engineered to encapsulate lipophilic TMCs. The incorporation of catalysts into these nanoparticle scaffolds creates water-soluble constructs that provide a protective environment for the catalyst. The potential therapeutic utility of these nanozymes was demonstrated through antimicrobial studies in which a cationic nanozyme was able to penetrate into biofilms and eradicate embedded bacteria through the bioorthogonal activation of a proantibiotic.
Bioorthogonal
activation of prodrugs provides a strategy for on-demand
on-site production of therapeutics. Intracellular activation provides
a strategy to localize therapeutics, potentially minimizing off-target
effects. To this end, nanoparticles embedded with transition metal
catalysts (nanozymes) were engineered to generate either “hard”
irreversible or “soft” reversible coronas in serum.
The hard corona induced nanozyme aggregation, effectively inhibiting
nanozyme activity, whereas only modest loss of activity was observed
with the nonaggregating soft corona nanozymes. In both cases complete
activity was restored by treatment with proteases. Intracellular activity
mirrored this reactivation: endogenous proteases in the endosome provided
intracellular activation of both nanozymes. The role of intracellular
proteases in nanozyme reactivation was verified through treatment
of the cells with protease inhibitors, which prevented reactivation.
This study demonstrates the use of intracellular proteolysis as a
strategy for localization of therapeutic generation to within cells.
This paper describes the fabrication of thermoresponsive bio-orthogonal catalytic systems though the integration of transition metal catalysts into gold nanoparticles. The confined assemblies of the catalysts provide a temperatureregulated system able to controllably activate antibiotics within biofilms. This work presents a blueprint for synthesizing a family of reversible thermoresponsive nanozymes with tailored activation temperatures and preserved bio-orthogonal activity in complex biological environments.
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