A tailored nanoplatform for eradicating resistant Pseudomonas aeruginosa and halting infection-driven pulmonary fibrosis

An inhalable core–shell nanoplatform is designed with pH-responsive release for dual modulation of host and pathogen. • A mucolytic polyglutamic acid shell enables efficient penetration of patient-derived mucus and biofilm disruption. • The polymer-based core delivers combinatorial antifibrotic and antibacterial agents in the acidic infection microenvironment. • The engineered nanocarrier eradicates resistant P. aeruginosa (>99%) and haltes infection-driven pulmonary fibrosis in vivo. Chronic pulmonary Pseudomonas aeruginosa ( P. aeruginosa ) infection in immunocompromised patients establishes a stubborn pathological triad of thickened mucus, dense biofilm, and excessive inflammation, driving pulmonary fibrosis and irreversible lung function decline. Current therapies, reliant on intensified antibiotics or nebulized polymyxin, fail to thoroughly disintegrate this triad, address the fibrotic drive, and exacerbate drug resistance. To address these challenges, we engineered inhalable nanoparticles (CPAP/PRIP NPs) with a layered structure, formulated using two custom-synthesized polymers. The pH-responsive core is self-assembled from a bactericidal and antioxidant/anti-inflammatory polymer (all-trans-retinal-ε-poly- l -lysine), which encapsulates the ion pairs composed of bactericidal polymyxin B (PB) and anti-fibrotic rhein. This ion-pairing strategy significantly enhanced the drug-loading efficiency of PB, while the pH-responsive design enables localized drug release specifically at infection sites (pH 5.5 to 6.5). To endow mucus-dissolving and penetrating capabilities, the core is further coated with a mucolytic/hydrophilic cysteamine-polyglutamic acid polymer shell. Nebulized CPAP/PRIP NPs exerted two key therapeutic actions: (i) efficiently eradicated difficult-to-treat-resistant P. aeruginosa (DTR P. aeruginosa ) via high drug loading, mucus dissolution and penetration, biofilm permeability, bactericidal activity, and virulence suppression; (ii) attenuated infection-driven pulmonary fibrosis via transforming growth factor β1 suppression and anti-inflammation/antioxidant effects. In vitro, CPAP/PRIP NPs disrupted the construction of patient-derived mucus, reduced its viscosity, and attenuated TGF-β1-driven pulmonary fibroblast invasiveness and migration. In vivo, CPAP/PRIP NPs ameliorated mucus layer, normalized cytokines, achieved over 99% eradication of DTR P. aeruginosa , and halted infection-driven pulmonary fibrosis. This integrated strategy represents an innovative approach for simultaneously eradicating DTR P. aeruginosa infection & halting infection-driven pulmonary fibrosis.