Active transfection of genetic materials using cyclodextrin-anchored nanovectors

Abstract

Gene-based therapy is a sophisticated means for the treatment of various complex diseases like AIDS, cancer, etc., as it resolves the genetic malfunction at the source instead of tackling the superficial symptoms. However, the therapeutic, diagnostic, and theranostic potential of gene-based therapeutic actives such as siRNA, mRNA, pDNA, aptamers, etc. is hindered by physicochemical as well as physiological barriers in the form of insufficient bioavailability, systemic metabolism, rapid renal clearance, inefficient carrier systems, etc. Although advanced carrier systems such as polyplexes, lipoplexes, dendriplexes, hydrogels, polyrotaxanes, etc. are employed to overcome such challenges, their structural configuration results in notable cytotoxicity to induce bio-incompatibility. In this context, strategic integration of cyclodextrins subdues the cytotoxicity by virtue of unique architectural characteristics and allows the fabrication of sophisticated systems for delivery of gene-based therapeutics. Inclusion of cyclodextrins offers benefits like enhanced protection of gene-targeted payloads, compact loading, nanoscale carrier dimensions, biostability, etc. by forming densely packed cargo systems. Cyclodextrins nullify the active cationic moieties to lower in vivo cytotoxicity and improve transfection efficiency across biomembranes. The multi-ligand binding capability of structurally-modulated cyclodextrins avails receptor specificity and gene-targeted therapeutic efficiency. The ability to form reversible covalent linkages allows the fashioning of multi-stimuli responsive supramolecular nanocarriers for a desirable drug release profile. The present review article features cyclodextrins and associated successful applications as the integral components of non-viral nanovectors such as cationic polymers, dendrimers and polyrotaxanes as well as supramolecular assemblies for efficient delivery of RNA-, DNA- and aptamer-based genetic payloads for the achievement of desired treatment outcomes.