Inhalable Nanosystems for Bacterial Respiratory Infections: Addressing Pulmonary Barriers and Biofilm-Associated Challenges.

Bacterial lower respiratory tract infections remain difficult to treat because effective antimicrobial concentrations must be achieved within complex and heterogeneous pulmonary microenvironments while minimizing systemic toxicity and addressing the growing challenge of antimicrobial resistance. These difficulties are further amplified by impaired mucociliary clearance, mucus hypersecretion, biofilm-associated tolerance, intracellular pathogen persistence, and non-uniform aerosol deposition. Inhalable nanosystems have therefore emerged as promising platforms to improve the local delivery of antibiotics and antibiofilm agents by prolonging pulmonary residence, modulating drug release, and enhancing interactions with specific biological barriers. This review provides a critical overview of the main classes of inhalable nanosystems investigated for bacterial respiratory infections, including natural and synthetic polymeric nanoparticles, polymeric micelles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, and nano-embedded inhalable formulations. Nanosystem composition, surface properties, drug-loading strategy, release behavior, and aerodynamic performance are discussed in relation to the biological niche of infection, including mucus-rich airways, extracellular biofilm-associated infections, and intracellular pathogens residing within macrophages. Particular attention is given to how these systems interact with pulmonary barriers and infection-related microenvironments, including mucus, biofilms, and intracellular bacterial niches. Selected emerging antimicrobial and antibiofilm approaches that may be integrated into inhalable nanosystems are also discussed. The main advantages and limitations of each platform are compared in terms of formulation performance, biological barrier interaction, pulmonary safety, manufacturability. Despite encouraging preclinical evidence, the clinical translation of inhalable nanosystems remains limited by formulation complexity, scale-up challenges, device compatibility, incomplete understanding of nanosystem-lung barrier interactions, and the lack of standardized infection and biofilm models predictive of clinical outcomes. Overall, this review highlights the need for a niche-guided and translationally oriented development of inhalable nanosystems, integrating antibacterial efficacy, pulmonary barrier interactions, inhalable formulation requirements, and manufacturability.