Inhalable nanoaerosols target the activation of HSP70 to regulate macrophage reprogramming for the treatment of bacterial pneumonia

This study addresses the intractable “infection-inflammation-injury” vicious cycle in MRSA pneumonia therapy. We have designed a glycosylated mesoporous polydopamine nanoaerosols (MPDA/B@M), which achieves effective treatment of MRSA infected pneumonia through multi mechanism synergistic effects. The aerosol encapsulates bufalin, an active component of traditional Chinese medicine, within MPDA carriers. Surface modification with mannose enables macrophage-targeted delivery. Upon inhalation, the aerosol accumulates efficiently in pulmonary lesions, directly killing pathogens via photothermal effects while releasing bufalin to suppress inflammation. Furthermore, MPDA/B@M scavenges excess ROS and upregulates heat shock protein 70 (HSP70) expression, providing dual cell-protective and anti-inflammatory effects. <em>In vitro</em> and <em>in vivo</em> studies demonstrate that MPDA/B@M nanoaerosols achieves 98.2% antibacterial efficacy against MRSA. In MRSA-infected murine pneumonia models, it significantly reduces pulmonary bacterial loads and reprograms macrophage phenotypes to modulate inflammatory responses. This integrated strategy synergizes targeted delivery, antibacterial action, oxidative stress modulation, and anti-inflammatory effects, offering an innovative solution for drug-resistant bacterial pneumonia.