Magnetothermal and ultrasound-activated nanoplatform for the inhalable therapy of bacterial lung infections

Antibiotic resistance in Klebsiella pneumoniae infections presents significant challenges in treating lung inflammation. To overcome tissue penetration barriers and modulate inflammatory responses, innovative therapeutic approaches are essential. This study introduces an inhalable nanoplatform, Fe_xS_y:Gd@PVP (FGP), based on polyvinylpyrrolidone-modified gadolinium-doped nonstoichiometric iron sulfide nanostructures. The platform integrates synergistic magnetic-ultrasound activation with magnetothermal therapy (mMHT), sonodynamic therapy (SDT), and gas therapy (GT) for targeted bacterial lung infection treatment. Gadolinium incorporation enhances the magnetothermal activation, improving magnetothermal conversion efficiency and sonodynamic performance by increasing magnetic anisotropy, narrowing the semiconductor bandgap, and enriching sulfur vacancies. Delivered via nebulized inhalation, FGP reaches infected lung tissues noninvasively. Exposure to alternating magnetic fields (AMF) and ultrasound (US) generates localized heat and reactive oxygen species (ROS), effectively eliminating bacteria. Simultaneously, AMF and US trigger hydrogen sulfide (H₂S) release in the acidic microenvironment, reducing inflammation by inhibiting inflammatory factors such as TNF-α and IL-1β through suppression of STAT3 and ERK phosphorylation. This magnetic-ultrasound co-activated inhalable nanoplatform offers a powerful multimodal therapeutic strategy for overcoming clinical challenges associated with bacterial lung infections. STATEMENT OF SIGNIFICANCE: This study introduces an inhalable nanoplatform that effectively treats multidrug-resistant Klebsiella pneumoniae lung infections. By integrating magnetothermal, sonodynamic, and gas therapies, this system eradicates bacteria and reduces inflammation. It uses gadolinium-doped iron sulfide nanostructures to enhance heat, reactive oxygen species, and hydrogen sulfide production, targeting deep lung infections precisely. Unlike traditional antibiotics, this noninvasive approach has minimal side effects and addresses both bacterial clearance and inflammation. This innovative strategy offers a promising solution for antibiotic-resistant infections and could revolutionize respiratory disease management.