Inflammation-responsive liposomes co-delivering tobramycin and nitric oxide for overcoming mucus barriers against MRSA pneumonia

An inhalable chitosan-coated liposomal system was developed for Tob/NO co-delivery. • LC@Tob/NO enhanced mucus penetration and enabled mildly acidic pH-responsive NO release. • Nebulized LC@Tob/NO disrupted MRSA biofilms and alleviated infected lung inflammation. Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia remains difficult to treat because mucus-associated transport barriers, biofilm formation, and excessive inflammation jointly limit therapeutic efficacy. Here, we developed a nebulizable chitosan-coated liposomal co-delivery system, LC@Tob/NO, for pulmonary treatment of MRSA pneumonia. The formulation integrates liposome-mediated pulmonary delivery, chitosan-associated surface reconstruction, tobramycin-mediated antibacterial activity, and mildly acidic inflammation-associated NO release from DETA/NO, thereby enabling localized Tob/NO co-loading for MRSA pneumonia therapy. LC@Tob/NO exhibited favorable physicochemical characteristics, enhanced transport through an artificial mucus matrix, and effective pulmonary deposition after nebulization. In vitro, the formulation showed potent antibacterial and antibiofilm activities against MRSA, while also attenuating oxidative stress and pro-inflammatory activation in macrophages. In a murine MRSA pneumonia model, nebulized LC@Tob/NO markedly reduced bacterial burden, alleviated lung edema and tissue injury, and suppressed inflammatory responses, with acceptable systemic biosafety. Supportive lung transcriptomic analysis suggested treatment-associated changes in immune and inflammatory pathways that were consistent with the observed bacterial clearance, cytokine reduction, and histological improvement. Collectively, LC@Tob/NO represents a promising inhalable biomaterial-based therapeutic strategy for MRSA pneumonia by integrating antibacterial activity with microenvironment regulation.