Self-Deliverable Peptide-Mediated and Reactive-Oxygen-Species-Amplified Therapeutic Nanoplatform for Highly Effective Bacterial Inhibition.

An "antibiotic-free strategy" provides a viable option to address bacterial infections, especially for the "superbug" challenge. However, the undesirable antibacterial activity of antibiotic-free agents hinders their practical applications. In this study, we developed a combination antibacterial strategy of coupling peptide-drug therapy with chemodynamic therapy (CDT) to achieve the effective bacterial inhibition. An amphiphilic oligopeptide (LAOOH-OPA) containing a therapeutic unit of (KLAK) peptide and a hydrophobic linoleic acid hydroperoxide (LAHP) was designed. The positively charged (KLAK) peptide with an α-helical conformation enabled rapid binding with microbial cells via electrostatic interaction and subsequent membrane insertion to deactivate the bacterial membrane. When triggered by Fe, moreover, LAHP could generate singlet oxygen (O) to elicit lipid bilayer leakage for enhanced bacteria inhibition. In vitro assays demonstrated that the combination strategy possessed excellent antimicrobial activity not only merely toward susceptible strains (Gram-positive and Gram-negative ) but also toward methicillin-resistant (MRSA). On the mouse skin abscess model induced by , self-assembled LAOOH-OPA exhibited a more significant bacteria reduction (1.4 log reduction) in the bioburden compared to that of the standard vancomycin (0.9 log reduction) without apparent systemic side effects. This combination antibacterial strategy shows great potential for effective bacterial inhibition.