An anionic PEGylated inulin-based carrier enables local pulmonary delivery of antibiotic colistin

Colistin (Col) is widely used to treat multidrug-resistant Gram-negative pulmonary infections, but its clinical efficacy is limited by poor mucus penetration, variable lung bioavailability, and systemic toxicity. This study developed an inulin (INU)-based graft copolymer as a nanocarrier to enhance pulmonary delivery, muco-diffusion, and controlled release of Col while preserving its antibacterial activity. INU was functionalized with a controllable substitution degree of succinic anhydride (SA) (DDSucc: 27–197 mol%) to obtain an ionizable derivative with carboxyl groups in side chains. The derivative with a DDSucc of 45 mol% was selected to graft 4 mol% of PEG chains, preserving ∼40 mol% of ionizable carboxyl groups. The resulting copolymer (INU-Succ-PEG) was able to electrostatically complex Col (nanocomplexes of ∼2 nm) and the aqueous dispersions showed excellent nebulization properties, with droplets <2 μm and a fine particle fraction >95%. Turbidimetric studies revealed reduced mucin interaction compared to free Col, enabling improved muco-diffusion. In vitro release studies demonstrated controlled drug release (<60% within 6 h), unaffected by mucin. The system showed good biocompatibility in bronchial cell lines. Antibacterial activity against K. pneumoniae and E. coli was preserved and superior to colistimethate sodium (CMS). Overall, the INU-Succ-PEG/Col system combines controlled release, high biocompatibility, improved mucus penetration, and optimal aerodynamic performance, representing a promising strategy for pulmonary treatment of chronic Gram-negative lung infections.