Inhalable nanohybrid of delpazolid enhances antimicrobial host defense against mycobacterial pulmonary infection.

Treatment of mycobacterial pulmonary diseases is challenged by long treatment durations and severe systemic toxicities of antibiotics such as oxazolidinones. Here, we developed an inhalable nanohybrid of delpazolid (DZD), termed DZD@DLC (a composite didodecyldimethylammonium bromide/lysozyme/chitosan system), to enhance local efficacy while mitigating systemic side effects. Specifically, this rationally designed platform integrates a cationic lipid core with a functional biopolymer shell, self-assembled into stable nanoparticles (∼80 nm) that promote DZD amorphization and enable pH-responsive drug release. In vitro, DZD@DLC demonstrated enhanced mycobacterial penetration, preferential uptake by infected macrophages, and a powerful synergistic antimicrobial effect. In vivo, pulmonary administration of DZD@DLC in murine infection models resulted in superior lung targeting and a more profound reduction in bacterial burden and inflammation compared to oral DZD. Critically, this enhanced efficacy was achieved while substantially mitigating the DZD-induced myelosuppression observed with systemic administration. DZD@DLC treatment preserved the hematopoietic stem cell pool and maintained a homeostatic myeloid profile in the bone marrow. By uncoupling therapeutic efficacy from systemic toxicity, the DZD@DLC nanohybrid represents a highly promising platform for developing safer and more effective inhalation therapies against challenging mycobacterial lung infections.