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 <i>Staphylococcus aureus</i> (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 <i>in vitro</i>. 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. <i>In vivo</i> 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.