Delivering antibiotics through pulmonary is a promising approach for treatment of cystic fibrosis (CF). For the current marketed antibiotic formulations, however, the requirement of multiple drug administrations per day to achieve a therapeutic effect limits their applicability. To reduce administration frequency, controlled pulmonary release formulation is a strategy which can maintain effective and consistent local drug concentration and therefore prolong the time period between doses. However, these particles of controlled release formulation with optimum aerodynamic diameter range targeted to the alveolar region (i.e. 0.5 < da < 5 μm) will be rapidly cleared by the alveolar macrophages. This is because the geometric diameters of these particles are usually less than 6 μm, which is the preferable size range for alveolar macrophages’ uptake. To overcome the clearance of alveolar macrophages for the controlled release formulation, the approach we employed in the current study was to form swellable hydrogel dry powder by utilizing the unique benefits of hydrogel, higher drug payload, larger geometric diameter after swelling, and sustained drug delivery. In the first study, based on the fact that ciprofloxacin could form hydrogel with alginate, a nano-in-micro hydrogel particle formulation was developed for sustained pulmonary drug delivery, which takes the advantages of both chitosan based nanoparticles and swellable and respirable alginate hydrogel particles. The dry nano-in-micro hydrogel particles exhibited a rapid initial swelling within 2 minutes, and showed sustained drug release pattern. When delivered to rats, it enabled ciprofloxacin to achieve a low systemic exposure but maintained higher concentrations in the lung for more than seven hours. In the second study, we directly combined ciprofloxacin with alginate to form hydrogel dry powder, without the addition of extra chitosan. In such way, we simplified the preparation method for hydrogel particles, decreased the potential risk of polymeric chitosan accumulation in the lung tissue, and increased the ciprofloxacin loading efficiency from 30% to 57% in the finial microsized alginate hydrogel dry powder. Ciprofloxacin was present in the amorphous state in the dry powder and was released in a controlled release manner relative to ciprofloxacin alone, i.e. 80% of drug released at 8 hours. Despite aggressive antibiotic treatment, the elimination of chronic Pseudomonas aeruginosa (P. aeruginosa) infections in CF lungs is extremely difficult. The pathogen often adapts to resist both the host inflammatory defense mechanisms and externally applied antibiotic therapy, often allowing for the formation of microbial biofilms. The resulting biofilms are thick, pathogen embedded, and highly resistant to common therapeutic agents currently used in CF infections. Thus, the development of newer antimicrobial agents with superior abilities to eliminate the established chronic biofilm associated with CF infections remains the utmost priority in CF therapy. A conventional antibiotic, tobramycin was chemically modified. Tobramycin has previously been demonstrated to bind to biofilm matrices, thus reducing the effective concentration of antimicrobial able to reach the pathogenic organisms, as well as limiting the penetration of the antibacterial agent to the deeper microstructure of the biofilm, thereby creating an undesirable stress response in the pathogen. Modification of antimicrobial as by PEGylation appears to be a promising approach for overcoming the bacterial resistance in the established biofilms of Pseudomonas aeruginosa. This body of work provides two promising strategies of delivering antibiotics via pulmonary route for the treatment of cystic fibrosis. The first strategy is to form controlled release formulation, typically as swellable hydrogel dry powder, which could sustain the drug release, and swell to larger size as to avoid the alveolar macrophage uptake as to increase the local retention period. The second strategy is related to the biofilm resistance. By modifying the existent antibiotic to reduce the binding efficacy to the extracellular matrix of biofilm, more antibiotic could subsequently enter into the inner region of bacterial colony.