A Smart Polypeptide-Based Photoresponsive Nanotherapeutic against Methicillin-Resistant <i>Staphylococcus aureus</i>

Abstract Therapeutic interventions for bacterial infections are increasingly challenging due to the growing threat of antibiotic resistance, particularly from Methicillin-resistant Staphylococcus aureus (MRSA), which poses significant risks to global health. Generally, MRSA has a high mortality rate and can lead to severe illnesses such as sepsis and pneumonia, mainly due to the lack of effective treatments and growing drug resistance. To this end, the present study introduces azobenzene-conjugated photo-responsive polypeptide nanofibers (PNFs) that mimic host-defense peptides to combat antibiotic-resistant bacterial pathogens. We show that incorporating an azobenzene moiety into the PNF enables light-mediated control via photoinduced conformational changes. The polypeptide structure incorporates these azobenzene units, synthesized via ring-opening polymerization (ROP) of N-carbobenzoxy-l-lysine N-carboxyanhydride (Cbz-l-Lys NCA) with NAP-AZO as the initiator. Moreover, we show that conformational changes in the PNF affect its interactions with bacterial membranes. While the azobenzene moieties provide light-regulated activity, the amino groups from lysine enhance electrostatic membrane disruption. This has resulted in effective membrane interaction of PNFs, facilitating the generation of reactive oxygen species (ROS) against MRSA, which are crucial for bacterial death or growth inhibition. Overall, the present study suggests that photo-responsive polypeptide PNFs represent a promising and versatile therapeutic strategy for combating antibiotic-resistant bacterial infections, owing to their dual functional capabilities.