Efficiently selective inactivation of Gram-positive bacteria by MCM-41 molecular sieve-supported copper-based self-cascading nanozymes

• MCM-41 serves as a carrier and neutralizes the positive charges of Cu 2 O nanozyme . • Negative MCM-41-Cu 2 O interacts electrostatically with Gram-positive bacteria. • MCM-41-Cu 2 O selectively kills S. aureus and B. subtilis with a bactericidal rate of 99.6%. • MCM-41-Cu 2 O continuously generates endogenous H 2 O 2 for POD-like catalytic reaction . • MCM-41-Cu 2 O has excellent biocompatibility and good in vivo antibacterial efficacy. Gram-positive bacteria can cause a variety of infectious diseases. Selectively inhibiting Gram-positive bacteria will avoid the misuse of broad-spectrum antibiotics, achieve precise treatment, and delay the development of antibiotic resistance. In this work, we successfully developed an MCM-41 molecular sieve-supported copper-based nanozyme composites (MCM-41-Cu 2 O) for selectively combating Gram-positive bacteria. MCM-41, with its porous structure and excellent biocompatibility, not only serves as a carrier but also neutralizes the positive charges of the metal nanozyme, endowing MCM-41-Cu 2 O with negative zeta potentials. This allows it to interact electrostatically with Gram-positive bacteria, facilitating the penetration of free radicals into the bacterial cell membrane, thereby killing the bacteria. MCM-41-Cu 2 O continuously generates endogenous H 2 O 2 through its glutathione oxidase (GSHOx)-like activity·H 2 O 2 serves as the substrate for peroxidase (POD)-like catalytic reactions, producing •OH radicals, thereby enabling a self-cascade reaction. This approach avoids the toxic side effects associated with excessive exogenous H 2 O 2 and offers higher biosafety with potential for antibacterial applications. DFT calculations reveal that compared to Cu 2 O, MCM-41-Cu 2 O exhibits greater adsorption and decomposition capacity for H 2 O 2 , accelerating reaction rates and enhancing POD-like activity. MCM-41-Cu 2 O selectively targets Gram-positive bacteria, achieving a bactericidal rate of up to 99.6% against S. aureus and B. subtilis while leaving E. coli and P. aeruginosa colonies largely unaffected. Reactive oxygen species (ROS) generated by MCM-41-Cu 2 O-5% disrupt bacterial membranes, leading to depolarization, protein leakage, and bacterial death. Additionally, the MCM-41-Cu 2 O nanocomposites exhibit excellent biocompatibility and demonstrate superior in vivo antibacterial efficacy compared to antibiotics, effectively treating wound infections caused by S. aureus . These findings position MCM-41-Cu 2 O as a promising alternative for treating infections caused by Gram-positive bacteria and provide new insights into the antimicrobial applications of molecular sieves.