Cell Wall-Binding Proteins-Armed Controlled-Release Nanodelivery System Enhances Nisin’s Efficacy against <i>Streptococcus pneumoniae</i> Infections

<i>Streptococcus pneumoniae</i> is a leading human pathogen responsible for life-threatening infections, particularly in children and the elderly worldwide. Current prevention and treatment strategies, including vaccines and antibiotics, are increasingly challenged by the emergence of nonvaccine serotypes and rising antibiotic resistance. Nisin, a lipid II-targeting peptide antibiotic, is effective against <i>S. pneumoniae</i> but suffers from instability at physiological pH, necessitating innovative delivery approaches. Here, we developed a nanodelivery system that enhances nisin's stability and efficacy by exploiting the acidic microenvironment of bacterial infections. This system utilizes oxidized hyaluronic acid and catechol chitosan to form a microenvironment-responsive nisin-loading module, further functionalized with a <i>S. pneumoniae</i>-specific endolysin cell wall binding domain (CBD_cpl-1) for targeted delivery. The system demonstrated significant infection site accumulation and controlled nisin release under acidic conditions, mimicking the infection environment. In a mouse model of antibiotic-resistant <i>S. pneumoniae</i>-induced pneumonia, the nanodelivery system significantly improved survival rates and reduced bacterial loads compared to free nisin, underscoring its potential as a powerful tool against antibiotic-resistant <i>S. pneumoniae</i> infections. This study presents a promising strategy for enhancing the clinical use of nisin and other peptide antibiotics, tackling the urgent challenge posed by resistant bacterial pathogens.