Functional Amyloid Phenol-Soluble Modulin α1-Targeting Photothermal Nanoplatform for Effective Elimination of Biofilm-Associated Infections

Biofilm-associated infections (BAIs) often lead to chronic infections and implant failure and are challenging to treat due to their resilience and complex structure, especially the extracellular polymeric substance (EPS). Phenol-soluble modulin α1 (PSMα1), a key biofilm-forming protein in methicillin-resistant Staphylococcus aureus (MRSA), can assemble into amyloid fibrils through self/cross-fibrillation and thus function as a scaffold that contributes to the integrity of the biofilm matrix. Here, using a phage display library-based biopanning strategy, we identified KG7, a PSMα1-targeting peptide that binds specifically to the fibrillation-dependent sequence in PSMα1, significantly inhibiting the amyloid fibrillation of PSMα1 and the subsequent biofilm formation in vitro. Further, the KG7 peptide was conjugated to the surface of polydopamine (PDA)-modified hollow copper sulfide (CuS) nanoparticles to develop an EPS-targeting photothermal nanoplatform (CuS@PPDA). This nanoplatform achieved a 94.7% biofilm inhibition rate and cleared 56.8% of mature biofilms through the regulation of PSMα1 fibrillation and the destruction of extracellular DNA, thanks to the synergistic effect of KG7-mediated inhibition and photothermal capability. Additionally, Cu2+ release from the nanoplatform regulated macrophage polarization toward the M2 phenotype. In vivo studies also demonstrated that this nanoplatform significantly accelerated diabetic wound healing and prevented biofilm formation on implants, along with excellent antibacterial performance and tissue regeneration efficiency. This work introduces a proof-of-concept of photothermal nanoplatform targeting biofilm-scaffolding amyloid PSMα1, offering a promising treatment for BAIs.