ABSTRACT
Introduction
Designing safe and effective nucleic acid delivery nanosystems presents a challenge that requires a good understanding of various biological barriers, whose impact is frequently neglected during in vitro assessments. Hence, the development of nanosizing non-viral vectors would benefit from a more thorough physicochemical characterization to establish structure–activity relationships and increase the preclinical data relevance.
Areas covered
This review focused on major barriers of lipoplexes and polyplexes by systemic delivery such as blood and immune cells and is aimed to serve as a prescreening tool for the fast and safe development of both non-viral vectors in vivo. An outline of the preclinical assays to be performed under physiological representative conditions, to better account for or even predict the highly dynamic interactions in humans is also given.
Expert opinion
The rational design of non-viral vectors has shown promising intracellular uptake results in vitro. Translating in vitro success into clinics has gone with progress, but it is still a difficult task to achieve, and more closely mimicking biological environment in vitro assays of lipoplexes and polyplexes may provide more correlated results to in vivo experiments. Clinical practice would benefit from safer non-viral vectors, particularly when avoiding patients' immune responses and toxicity, which is of major concern.
Article highlights
Despite advances in lipoplexes and polyplexes, clinical trials are still limited due to obstacles with their toxicity and immune detection.
Protein corona impact on non-viral vectors can change their blood and immune compatibility properties.
The non-viral vectors LPNs portrayed the benefits of a rational approach and drive the development of other acid nucleic delivery systems.
Recent studies revealed that in terms of delivery efficiency and toxicity, distinct polymers have drastic differences.
Recent formulations of lipoplexes and polyplexes still demonstrate an unsystematic approach regarding blood and immune compatibility testing.
Some formulations present cytokine induction while demonstrating high levels of cell viability.
This box summarizes key points contained in the article.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers of this manuscript have no relevant financial or other relationships to disclose.
List of abbreviations
ABC – Accelerated blood clearance
AMBP – Alpha-1-microglobulin/bikunin precursor
APC(s) – Antigen-presenting cell(s)
ApoE – Apolipoprotein E
BPEI – Branched polyethyleneimine
CD4+ – Cluster of differentiation 4
CD8+ – Cluster of differentiation 8
DLS – Dynamic light scattering
DODMA – 1,2-dioleyloxy-3-dimethylaminopropane
DOPC – 1,2-dioleoyl-sn-glycero-3-phosphocholine
DOPE – 1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine
DOTAP – 1,2-dioleoyloxy-3-trimethylammonium propane
DOTMA – 1,2-di-O-octadecenyl-3-trimethylammonium propane
DSPC – 1,2-Distearoyl-sn-glycero-3-phosphocholine
DSPE – 1,2-distearoyl-sn-glycero-3-phosphoethanolamine
EPR – Enhanced permeability and retention effect
FBS – Fetal bovine serum
FDA – Food and Drug Administration
FSC – Fluorescence correlation spectroscopy
GMP – Good manufacturing practices
HBPE-SO3 – Hyperbranched polyester nanoparticles-sulfonic acid functional groups
IFN-γ – Interferon gamma
IgM – Immunoglobulin M
IL-1β – Interleukin 1beta
IL-6 – Interleukin 6
IL-12 – Interleukin 12
kDa – Kilo dalton
LNP(s) – Lipid nanoparticle(s)
mRNA – Messenger ribonucleic acid
NCL – Nanotechnology Characterization Laboratory
NK cells – Natural killer cells
NTA – Nano tracking analysis
PBAE – Poly-β-amino esters
PCB – Polycarboxybetaine
pDNA – Plasmid deoxyribonucleic acid
PEG – Polyethylene glycol
PEI – Polyethylenimine
pKa – Acid dissociation constant
PLGA – Poly lactic-co-glycolic acid
PLL - Poly-L-lysine
RISC – RNA-induced silencing complex
SEM – Scanning electron microscopy
siRNA – Short interference ribonucleic acid
SNALP – Stable nucleic acid lipid particles
SNL(s) – Solid lipid nanoparticle(s)
TEM – Transmission electron microscopy
TNF-α – Tumor necrosis factor alfa