Cu2+-doped Hollow Ca2+-polyphenol nano-therapeutics for overcoming multidrug-resistant bacteria-induced infections

The abuse of antibiotics has accelerated the emergence of multidrug-resistant (MDR) bacterial strains, while the development of novel antibiotics has failed to keep pace with the evolution of bacteria. Consequently, there is an urgent need to develop innovative alternative antibacterial materials to combat drug-resistant bacterial infections. Herein, we fabricate Cu²⁺-doped hollow Ca²⁺-tannic acid nanoparticles (ATA@Cu NPs) with pH-sensitive drug release behavior to effectively eliminate MDR bacteria at acidic infection sites. Under a pH 6.0 environment that simulates the infection microenvironment, the ATA@Cu NPs can release the Cu²⁺ to potently eradicate methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MRPA). Notably, owing to the excellent intracellular drug delivery property, ATA@Cu NPs exhibit potent bactericidal efficiency against intracellular bacteria. Furthermore, the ATA@Cu NPs demonstrate commendable therapeutic performance in treating MRPA-infected keratitis, as they significantly alleviate the bacterial burden by diminishing 4.0 logs of MRPA, promote the recovery, and restore normal corneal structure. Additionally, using a self-made nebulization device, the ATA@Cu NPs display robust therapeutic efficiency in combating MRSA-induced pneumonia and eliminating intracellular MRSA with a 2.8 log reduction via pulmonary delivery. Therefore, this study fabricates pH-responsive Cu²⁺-doped hollow Ca²⁺-polyphenol nano-therapeutics to combat MDR bacteria-induced infection, thereby providing a potential therapeutic strategy to address the challenges of MDR bacteria in the future.