# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 5 Nanocarriers for CF Treatment  
For several years, different therapeutic strategies have been identified to improve the efficiency of CF treatment. Various gene-based and non-gene-based therapeutics have proven to be promising approaches for the treatment of CF [176; 177; 178; 179]. Despite the enormous developments in the management and treatment of CF in recent years, several challenges still exist. One of the primary challenges is the successful delivery of these therapeutics to the target organ. Gene-based therapeutics face the problem of low stability in body fluids since they are degraded by nucleases [180]. Moreover, the off-target effect limits the in vivo application of gene-based therapeutics [177]. In contrast, non-gene-based therapeutics have limitations such as rapid clearance from the body, low stability, and high toxicity during the administration of a large dose. Significant progress in the field of nanotechnology has led to the discovery of nanocarriers, which will improve the current therapeutic strategies for CF treatment and open doors for the development of innovative approaches. Nanocarriers offer a  
Figure 5: Therapeutic approaches for CF. (**a**) Targeting bacterial biofilm: Bacterial infection in CF is associated with the formation of a biofilm that resists the host immune system as well as antibiotics. Antibioticfilm therapy is essential to prevent bacterial colonization and adherence. (**b**) Direct therapy for CFTR: Faulty CFTR is corrected by gene therapy, wherein CFTR is delivered as cDNA or mRNA using a viral or non-viral vector. Another approach is the use of antisense oligonucleotide molecules to repair the mRNA encoded CFTR. Small molecule modulators, like potentiator, stabilizer, corrector, and amplifier are considered as promising agents for the restoration of CFTR function. (**c**) Indirect therapy targeting the hyperactivated ENaC: In CF, owing to the loss of CFTR regulation, the sodium channel (ENaC) is hyperactivated, leading to the dehydration of the mucus layer. Inhibiting ENaC expression using siRNA, antisense oligonucleotide molecules, or small molecule modulators can correct the mucociliary defect. novel strategy to enhance the delivery of therapeutics for CF patients. The implementation of nanotechnology in designing therapeutic vehicles primarily improves the specificity for the drug target cells, thereby reducing unexpected side effects. Inhalation formulations have been used extensively in CF patients for the local delivery of therapeutics (i.e., antibiotics) to the lungs, evading obstacles like hepatic and renal clearance that are associated with the parenteral administration of these medications [181]. Numerous studies have focused on the promising features of nanoparticles as carriers for the delivery of gene- and non-gene-based molecules via inhalation, to enhance the treatment efficiency and reduce toxicity [182; 183]. The field of nanotechnology has overcome the complexity of the pulmonary system with its different biological and physiological barriers, including respiratory tract, epithelial layers, mucus, and bacterial biofilm [184]. However, the biocompatibility and biodegradability of materials used for the production of inhalable nanoparticles must be considered before developing novel inhaled products for CF treatment [185]. One of the barriers for CF therapy is the thick mucus layer present within the alveolar region that prevents the penetration of the nanoparticles to the target cells [67]. The mucus layer consists of different components like mucin fibers, DNA, and actin, which form a crosslinked network of mesh size 100-200 nm in CF patients and 500 nm in healthy individuals [186]. Nanoparticles should be small enough to avoid steric inhibition by the dense fiber mesh and also to avoid adhesion to mucin fibers in order to penetrate mucus successfully [187]. The application of nanoparticles of less than 100 nm enhances the penetration of therapeutic molecules through the mucus layer [187; 188].