Nanovalves-Based Bacteria-Triggered, Self-Defensive Antibacterial Coating: Using Combination Therapy, Dual Stimuli-Responsiveness, and Multiple Release Modes for Treatment of Implant-Associated Infections

Preventing implanted stainless steel (SS)-associated bacterial infections remains a critical challenge. In this study, we report a novel nanovalves-based, bacteria-triggered, and self-defensive antibacterial coating (NV-BT-SDAC), which integrates pH/enzyme dual-stimuli responsiveness, combination therapy, and multiple release modes, and accurately execute controlled release of antimicrobials only when bacteria adhere to the implant surface. The vertically aligned mesoporous silica coating was first deposited on the surface of SS 316L. After successive functionalization with (3-aminopropyl)-triethoxysilane, succinic anhydride, propynol ethoxylate, and monopyridine functionalized β-cyclodextrin as nanovalves, NV-BT-SDAC was constructed. We simultaneously loaded cinnamaldehyde (CA) and ampicillin (AMP) into the perpendicular mesochannels of NV-BT-SDAC to demonstrate combination antibiotic therapy against bacterial infections. Under normal physiological environments, the cage-like structures comprising nanovalves and functional linkages seal the pore orifices to prevent leakage of antimicrobials. Upon applying pH/enzyme stimuli, which often emerge in local infection sites, three different release modes were obtained: (i) pH-triggered release of CA by virtue of reversible structural transformation of nanovalves; (ii) enzyme-triggered corelease of CA and AMP due to the cleavage of functional linkages; and (iii) sequential release of CA and AMP by the ordered action of pH and enzyme stimuli. When attacked by Staphylococcus aureus, Escherichia coli, or methicillin-resistant Staphylococcus aureus, NV-BT-SDAC exhibited excellent antibacterial and antiadherent activities. The pH/enzyme dual-stimuli responsiveness enhanced response sensitivity, and synergistic interaction between CA and AMP demonstrated satisfactory antibacterial activity against antibiotics-resistant bacteria. Moreover, the cooperation of combination therapy and multiple release modes has the potential to retard the emergence of pathogenic resistance in clinical trials.