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 _D(KLAK)₂ peptide and a hydrophobic linoleic acid hydroperoxide (LAHP) was designed. The positively charged _D(KLAK)₂ 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 Fe²⁺, moreover, LAHP could generate singlet oxygen (¹O₂) 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 Staphylococcus aureus and Gram-negative Escherichia coli) but also toward methicillin-resistant Staphylococcus aureus (MRSA). On the mouse skin abscess model induced by S. aureus, self-assembled LAOOH-OPA exhibited a more significant bacteria reduction (1.4 log₁₀ reduction) in the bioburden compared to that of the standard vancomycin (0.9 log₁₀ reduction) without apparent systemic side effects. This combination antibacterial strategy shows great potential for effective bacterial inhibition.