Keeping steps ahead of the bacteria in the race for more efficacious antibacterial strategies is increasingly difficult with the advent of bacterial resistance genes. Herein, we engineered copper sulfide nanoclusters (CuSx NCs) with variable sulfur defects for enhanced dual-treatment of bacterial infections by manipulating photothermal effects and Fenton-like activity. Next, by encasing CuSx NCs with a complex mixture of amino acids and short peptides derived from Luria-Bertani bacterial culture media as a protein corona, we managed to coax E. Coli to take up these CuSx NCs. As a whole, Amino-Pep-CuSx NCs was perceived as a food source and actively consumed by bacteria, enhancing their effective uptake by at least 1.5-fold greater than full length BSA protein BSA-corona CuSx NCs. Through strategically using defect-engineering, we successfully fine-tune photothermal effect and Fenton-like capacity of CuSx NCs. Increased sulfur defects lead to reduced but sufficient heat generation under solar-light irradiation and increased production of toxic hydroxyl radicals. By fine-tuning sulfur defects during synthesis, we achieve CuSx NCs with an optimal synergistic effect, significantly enhancing their bactericidal properties. These ultra-small and biodegradable CuSx NCs can rapidly break down after treatment for clearance. Thus, Amino-Pep-CuSx NCs demonstrate effective eradication of bacteria both in vitro and in vivo because of their relatively high uptake, optimal balanced photothermal and chemodynamic outcomes. Our study offers a straightforward and efficient method to enhance bacterial uptake of next generation of antibacterial agents.
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