# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 5 Nanocarriers for CF Treatment
Dendrimers can be formulated as DPIs or suspensions for administration via inhalation in CF patients [211]. As previously mentioned, _P. aeruginosa_ infection, which is known to form biofilms and possess antimicrobial resistance, is considered as a serious complication in CF [212]. The cysteamine drug (Lynovex(r), Novabiotics), an oral mucoactive, antibiofilm, and antibacterial agent, has passed the phase IIb clinical trial (NCT03000348) for use in the treatment of acute, infectious CF exacerbations [213]. PAMAM dendrimers were modified as cysteamine-like structure dendrimers (PAMAM-DEN\({}^{\text{CYS}}\)), to obtain the antibiofilm activity of cysteamine [214]. PAMAM-DEN\({}^{\text{CYS}}\) demonstrated enhanced penetration across the thick mucus layer, thus, reducing biofilm formation, and the infection associated with _P. aeruginosa_[214]. A recent study by [PERSON] et al. (2019) has confirmed the novel activity of PAMAM-DEN\({}^{\text{CYS}}\) in inhibiting _P. aeruginosa_ infection, and its role in the progression of CF therapy with respect to the recovery of F508 del-CFTR in the plasma membrane [215]. Exosomes have attracted attention as novel drug delivery systems owing to their unique composition [216]. They are nanosized, extracellular vesicles (EVs) with mean diameters ranging from 50 to 200 nm, and properties similar to that of unilamellar (single-layered) liposomes [217]. Exosomes are secreted from different cell types and exhibit novel properties like specific cell targeting ability and homing selectivity, which primarily depends on the cell from which it originated [218]. The lipid bilayer of exosomes is composed of different types of phospholipids (i.e., glycosphingolipid ganglioside GM3, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine). This structure protects the loaded drugs from the opsonin protein and other immune components. Hence, it reduces the interaction with blood components and mediates the delivery of biomolecules and genetic materials to the target cells [219]. The surface of exosomes contains several essential proteins and ligands like integrins and tetraspanins, which have an intrinsic function of inducing the cellular internalization of therapeutics to the target sites [220; 221]. A recent study has demonstrated the treatment of human nasal epithelial cells of F508 del CF patients with the CRISPR/dCas-VPR and BGas-gapmer systems (BGas is a long, non-coding RNA involved in transcriptionally modulating CFTR expression with a gapmer) via the activation of endogenous CFTR. This gapmer was loaded inside exosomes isolated from A549 cells and lipid-based nanoparticles. The study findings revealed enhanced expression of the CFTR following the application of both nanoparticles. However, the expression was higher in exosomes compared to lipid-based nanoparticles [180]. The composition of exosomes can be therapeutically effective, in which they give a synergistic effect when they are used as nanocarriers. It was reported that the intratracheal administration of EVs, such as exosomes that are originated from mesenchymal stem cells (MSCs), can be an effective treatment for bronchopulmonary dysplasia (BPD) in an animal model [222]. In their study, the number of alveoli in the BPD animal model was significantly increased when these EVs were administrated intratracheally. Another study demonstrated an in vitro dose-dependent efficacy of EVs that are originated from adipose MSCs contain alpha 1 antitrypsin protein, which is known for its role in the lung as an elastase inhibitor [223]. Furthermore, EVs from adipose MSCs contain approximately 46 proteins which have antibacterial activities against Gram-negative bacteria such as _P. aeruginosa_ and _Klebsiella_[223]. Despite the significant advantages of using nanocarriers in the delivery of gene-based and non-gene-based therapeutics in CF patients, certain challenges still exist.