An overview of nanosomes delivery mechanisms: trafficking, orders, barriers and cellular effects

Figures & data

Figure 1. (a) Drug delivery nanosomes can be actively targeted to specific cells by ligand labelling such as folic acid, transcobalamin, iron transport proteins, hormones and growth factors to facilitate their active cellular import. Furthermore, the cargoes can be localized in subcellular location using specific organelle localization signal. Tumour cells can be passively targeted to using effect retention and permeability effect. (b) First-level drug delivery is the targeting of nanosomes to the capillary bed of a predetermined organ or tissue (green colour). Second-level targeting is the selective delivery of drugs to specific cell types such as tumour selective drug delivery to Kupffer cells in the liver (blue colour). Third-level targeting is drug delivery specifically to an intracellular site such as organelle targeting (red colour). Fourth level is drug delivery specifically to an intra-organelles compartment (yellow colour).

Table 1. The common nanosomes (NS) used as drug delivery cargoes with common cargo.

Cargoes	Composition	Common Payload	Notes
Endosome	Endocytosis substances	Endogenous or exogenous	Endocytotic origin
Caveosome	Endocytosis substances	Endogenous or exogenous	Endocytotic origin
Exosome	Cell like structure	Proteins, and others	Cell communication, Drug cargo
Hybrid exosome	Cell like structure	Drug	Novel Drug cargo
Proteosome	Protein	Damaged proteins	Protein degradation system
Nucleosome	DNA + Protein	DNA	DNA wrapping
Genosome	DNA + liposome	DNA acting drugs	Nuclear delivery
Virosome	Viral derived	DNA acting drug	Gene therapy vector
Liposome	Phospholipids	Hydrophilic and Lipophilic drugs	Drug cargoes
Sphingosome	Sphingolipids	Hydrophilic and lipophilic drugs	Target drug cargoes
Erythrosome	RBCs like structure	Drugs	Drug cargo, biological coat
Niosome	Non-ionic surfactant, cholesterol	Hydrophilic and Lipophilic drugs	Easily prepared and stable

All of these cargoes can be targeted tumour cells or specified cell using targeting moieties such as antibodies or antibody fragments, peptides, folic acid, cobalamin, transferrin and sugars, due to the presence of receptor for such ligand in specified cell or cancer cell. Usually the ligands labelled cargoes targeted receptor mediated-endocytosis. SLNs: indicated that solid lipid nanoparticles, NLCs: nanostructured lipid carriers.

Table 2. Checkpoints that face nanosomes (NS) during their journey from first level to final destination.

Type of barriers	Examples	Location	Escape strategies
Universal checkpoints	Protein corona, PGP, PMS, and metabolizing enzymes.	Ubiquitous distributed	NS stealth, PGP inhibition and enzymes inhibitors
Specific checkpoints	GI milieu, mucociliary escalator, BBB, stratum corneum and others.	Organs specific	Special tactics during NS fabrication
Cellular checkpoints	Tight junctions, ECM, glycocalyx and efflux transporters.	Cell membrane	CPP, ligand, very small NS and cationic NS
Intracellular checkpoints	Lysosomes, cytoplasmic crowding and binding to intracellular components	Intracellular	Endosomal escape using proton sponges, CPP, and others

Figure 2. Road map of nanosomes import and export across biological membranes. Abbreviations: CME: Clathrin-mediated endocytosis; CvME: Caveolae-mediated endocytosis; CCIE: clathrin- and caveolae-independent endocytosis; UPME: ubiquitin mediated endocytosis.

Figure 3. Endocytotic and exocytotic machinery of nanosomes, both of CME and CvME internalize cargoes across biological membranes. In particular those labeled with folic acid, transcobalamin, transferrin, hormones and growth factors. CME is the predominant path of internalization for positively charged nanosystems. However, CvME is recommended as portal for entry for anionic nanosystems. Thus, nano-drug delivery cargoes can be actively targeted to specific cells. The CCIE pathway of nanosystem import does not depend on the presence of clathrin or caveolin in the import of nanosystems. After internalization, the vesicles containing nanosystems are recycled to the plasma membrane, or targeted to late endosomes and later to lysosomes. The cargoes labelled to organelles targeting must escape the lysosomal degradation. Finally, nanosystems are exocytosed as elements, or as natural nanocarriers in the form of exosomes, microvesicles, or apoptosome.