Abstract
Cationic liposomes (CLs) are effective carriers of a variety of therapeutics. Their applications as vectors of nucleic acids (NAs), from long DNA and mRNA to short interfering RNA (siRNA), have been pursued for decades to realize the promise of gene therapy, with approvals of the siRNA therapeutic patisiran and two mRNA vaccines against COVID-19 as recent milestones. The long-term goal of developing optimized CL-based NA carriers for a broad range of medical applications requires a comprehensive understanding of the structure of these vectors and their interactions with cell membranes and components that lead to the release and activity of the NAs within the cell. Structure–activity relationships of lipids for CL-based NA and drug delivery must take into account that these lipids act not individually but as components of an assembly of many molecules. This review summarizes our current understanding of how the choice of the constituting lipids governs the structure of their CL–NA self-assemblies, which constitute distinct liquid crystalline phases, and the relation of these structures to their efficacy for delivery. In addition, we review progress toward CL–NA nanoparticles for targeted NA delivery in vivo and close with an outlook on CL-based carriers of hydrophobic drugs, which may eventually lead to combination therapies with NAs and drugs for cancer and other diseases.
Highlights
Amphiphilic molecules, i.e., molecules with a polar, hydrophilic headgroup and a hydrophobic tail or tails, spontaneously self-assemble in water, primarily due to hydrophobic interactions [1]
Similar to DOTAP/DOPE–DNA complexes (Figure 8b), varying the preferred curvature of the lipid mixture forming Cationic liposomes (CLs)–short interfering RNA (siRNA) by means of changing the ratio of DOTAP (C0 = 0) and DOPE (C0 < 0), makes it possible to steer the phase of the resulting CL–siRNA complexes toward lamellar
Studies revealed that CL–DNA complexes displayed increased transfection efficiency (TE) if the cationic lipid was combined with a neutral lipid. (TE is a measure of the extent of expression of an exogenous gene that is transferred into the cell)
Summary
Amphiphilic molecules, i.e., molecules with a polar, hydrophilic headgroup and a hydrophobic tail or tails, spontaneously self-assemble in water, primarily due to hydrophobic interactions [1]. MicroRNA [59], gene editing via CRISPR/Cas-9 [60,61,62], and expression of basemodified mRNA [63,64,65,66,67,68,69,70], have greatly expanded the therapeutic potential of NAs. The first culmination of these efforts was the FDA approval of a lipid-based siRNA vector (patisiran/ONPATTRO® , Alnylam Pharmaceuticals) in 2018 for treatment of the polyneuropathy caused by hereditary transthyretin amyloidosis [71,72]. In addition to the fact that complex formation with CLs protects NAs from degradation, an early rationale for utilizing cationic rather than neutral or negative liposomes to deliver DNA was that CL–DNA complexes designed to have an overall positive charge (i.e., with a lipid/DNA charge ratio > 1) would electrostatically adsorb to anionic mammalian cells, leading to cellular binding and more efficient uptake [8]. The lipid/DNA charge ratio refers to the number of charges on the lipid divided by the number of charges on the DNA (under the conditions that the lipid and DNA are combined)
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