# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 5 Nanocarriers for CF Treatment
This strategy was used to correct the defective chloride transport in CF patients [146]. Subsequently, more viral vectors like AAV emerged in CF treatment. AAV showed a high transduction efficiency compared to AV. It has been reported that the delivery of an integrated AAV-based CFTR expression vector in a CF animal model stabilized the expression of CFTR and corrected the defects in the anion transport system [196]. Despite the use of viral vectors for the delivery of therapeutics, several limitations have been identified. The high immunogenicity, low loading efficiency, and production complications of viral vectors have promoted researchers to find a safer and more efficient drug delivery system [197]. Non-viral vectors like liposomes, solid lipid nanoparticles (SLNs), polymers, and dendrimers have been commonly used for gene and drug delivery in CF patients. The crucial features of non-viral vectors are their low immunogenicity, easy fabrication, low production cost, and their ability to load both non-gene and gene-based therapeutics. Liposomes are one of the most commonly used non-viral delivery systems that are exploited as nanocarriers in CF treatment. Liposomes consist of a lipid bilayer with hydrophilic heads and hydrophobic tails. The hydrophilic heads are orientated toward the aqueous core, a bulky environment. Different drugs, antibiotics, peptides, and nucleic acids are entrapped or complexed with liposomes and have been tested as inhalation delivery systems in CF treatment. Local administration improves the therapeutic efficacy of the loaded drugs [197]. Their biocompatibility and ability to encapsulate hydrophilic and lipophilic compounds are the primary advantages of liposomes. The encapsulation of drugs by liposomes increases their bioavailability and reduces cellular toxicity by decreasing the required therapeutic dose. Plasmid DNA (pDNA), siRNA, and other therapeutic molecules used in gene therapy suffer from low stability and difficulty in crossing the cell membrane to reach the site of action. These aspects could be overcome using liposomes. A phase IIb clinical trial (NCT00789867) has reported that the complexing of pDNA (pGM169) with the cationic liposome, GL67A, enabled successful drug delivery in CF patients with enhanced FEV1, using commercially available nebulizers [198]. Using cationic liposomes for the delivery of antibiotics or antibioofilm peptides enhances the electrostatic interaction with biofilm-forming bacteria, allowing longer drug residence time with the pathogen. These key features of liposomes have opened doors for the design of novel therapeutic strategies to develop an efficient non-viral delivery system targeting CF. The transfections of primary CF epithelial cells with cationic liposomes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) complexed with siRNA of \(\alpha\) and \(\beta\)-subunit of ENaC has successfully corrected the mucociliary defects while increasing the ASL depth [176]. In another study, targeting of \(\alpha\)-subunit of ENaC in CF patients, using a cationic liposomal-siRNA complex conjugated with the target peptide (hydrodynamic size \(192\ \pm\ 4\) nm and \(\zeta\) potential \(23.6\ \pm\ 0.4\) mV), has modulated the Na\({}^{+}\) ion hyperabsorption, thereby, restoring the mucus hydration and correcting the mucociliary defects [173]. Two amikacin (an aminoglycosoxide antibiotic)-loaded liposomal formulations, ARIKACE(tm) and ARIKAYCE(tm), that are composed of dipalmitoyl phosphatidylcholine (DPPC) lipid and cholesterol have successfully reached the clinical trials [199; 200]. ARIKAYCE(tm) has reached phase IIa clinical trial (NCT03905642) after evaluating 49 participants, whereas ARIKACE(tm) has reached phase III clinical trial (NCT01316276) after evaluating 206 participants. Both liposomal formulations have shown better diffusion across the mucus layer than the free drug and were able to deposit the loaded antibiotic in the targeted _P. aeruginosa_ biofilm.