Light-Triggered Bioorthogonal Nanozyme Hydrogels for Prodrug Activation and Treatment of Bacterial Biofilms

Bioorthogonal nanozymes offer in situ activation of pro-dyes and prodrugs using abiotic chemical transformations. Bacterial infections, especially biofilm-associated infections, are extremely difficult to treat due to obstacles such as poor antibiotic penetration and the rising threat of antibiotic resistance. Spatiotemporal control of bioorthogonal catalysis provides a strategy for "on-demand" generation of therapeutics, effectively localizing therapeutic action and minimizing side effects. Here, we present the fabrication of visible-light-responsive alginate hydrogel beads embedded with bioorthogonal polyzymes (PZs). Exposure to a 405 nm light induces the reduction of Fe(III) to Fe(II), triggering the dissolution of the <b>PZ</b>-<b>gel</b> beads with concomitant release and activation of the polyzyme. This approach enabled the selective activation of a prodrug of Linezolid, a last-in-line antibiotic for Gram-positive bacterial infections, enabling the targeted eradication of multidrug-resistant<i>Staphylococcus aureus</i> biofilms. Overall, the use of alginate biomaterial along with noninvasive visible light offers a nontoxic platform for spatiotemporal release of antibiotics through bioorthogonal activation.