In Vitro and in Vivo mRNA Delivery Using Lipid-Enveloped pH-Responsive Polymer Nanoparticles

Abstract

Biodegradable core-shell structured nanoparticles with a poly(β-amino-ester) (PBAE) core enveloped by a phospholipid bilayer shell were developed for in vivo mRNA delivery, with a view toward delivery of mRNA-based vaccines. The pH-responsive PBAE component was chosen to promote endosome disruption, while the lipid surface layer was selected to minimize toxicity of the polycation core. Messenger RNA was efficiently adsorbed via electrostatic interactions onto the surface of these net positively-charged nanoparticles. In vitro, mRNA-loaded particle uptake by dendritic cells (DCs) led to mRNA delivery into the cytosol with low cytotoxicity, followed by translation of the encoded protein in these difficult-to-transfect cells at a frequency of ~30%. Particles loaded with mRNA administered intranasally in mice led to the expression of the reporter protein luciferase in vivo as soon as 6 h after administration, a timepoint when naked mRNA given i.n. showed no expression. At later timepoints, luciferase expression was detected in naked mRNA-treated mice, but this group showed a wide variation in levels of transfection, compared to particle-treated mice. This system may thus be promising for non-invasive delivery of mRNA-based vaccines.

Zerumbone-loaded nanostructured lipid carrier induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in a human lymphoblastic leukemia cell line

“…Since ZER-NLC is intended for parenteral use, the potential toxic effect of the compound was assessed by in vitro and in vivo assays. 16 We demonstrated that the anticancer activity of zerumbone is not affected or impaired by incorporation into an NLC. Upon administration, zerumbone is immediately available to target cells, whereas the ZER-NLC needs to be internalized into cells via endocytosis or phagocytosis and degraded before zerumbone is released from the nanoparticles to produce an effect.…”

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come

“…Moreover, only a low encapsulation efficiency of water-soluble substances can be achieved because of the leakage of these substances into the aqueous phase (Su et al, 2011). To improve the range of substances to be encapsulated, ESE must be used.…”

Functional RNA Delivery Targeted to Dendritic Cells By Synthetic Nanoparticles

“…Another successful modification was to coat pH-responsive polymer particles with a lipid envelope [104], but this approach adsorbed the mRNA to the surface of the particles, which could prove problematic due to the sensitivity of mRNA to RNAases. Improved RNA stability, together with enhanced transfection efficiency and reduced toxicity, was observed with co polymer blends of PEI and PEI-PEG and cationic lipids DOTAP and DOPE [105,106], although no DC targeting was reported.…”