A Sonosensitizer‐Cationic Polypeptide Conjugate Potentiates Sonodynamic Therapy for Mature Biofilm Eradication and Periodontitis Treatment

ABSTRACT Periodontitis, a leading cause of adult tooth loss, requires effective plaque biofilm removal for successful treatment. Conventional mechanical debridement often fails to eradicate biofilms from deep root surfaces, leading to disease recurrence. Sonodynamic therapy (SDT) has emerged as a promising noninvasive antibacterial approach, owing to its capacity for deep tissue penetration. However, the efficacy of SDT is limited by the insufficient penetration of sonosensitizers through the dense extracellular polymeric substances of biofilms. Herein, a sonosensitizer‑cationic polypeptide conjugate (PPa‑cP) was developed via simple ring‐opening reactions. The cationic design facilitated electrostatic binding to embedded bacteria within the biofilm, significantly enhancing sonosensitizer localization and the subsequent ultrasound‐triggered bactericidal effect. PPa‑cP achieved a reduction of >99.8% in viable bacteria within mature Porphyromonas gingivalis and Fusobacterium nucleatum biofilms. Transcriptomic analysis further revealed that PPa‐cP disrupted Porphyromonas gingivalis at structural, metabolic, and functional levels. In a rat periodontitis model, PPa‑cP significantly attenuated alveolar bone resorption and inflammatory responses. This work demonstrates a promising SDT conjugate with potential for treating periodontitis and other biofilm‑associated infections.