Abstract
Systemic messenger RNA (mRNA) delivery, although still in its infancy, holds immense potential for application in cancer vaccination and immunotherapy. Its advantages over DNA transfection make it attractive in applications where transient expression is desired. However, this has proved challenging due to mRNA’s instability and susceptibility to degradation. Selenium is important for immune function and modulation, with selenium nanoparticles (SeNPs) finding a niche in biomedicine as drug delivery vehicles, owing to their biocompatibility, low toxicity, and biodegradability. In this investigation, we synthesized chitosan-coated SeNPs with a folic acid targeting moiety for Fluc mRNA delivery to cancer cells in vitro. Synthesized SeNPs were stable and well dispersed, and ranged from 59 to 102 nm in size. Nanoparticles bound and protected mRNA from RNase degradation, while exhibiting low cytotoxicity in the human embryonic kidney (HEK293), breast adenocarcinoma (MCF-7), and nasopharyngeal (KB) cells in culture. Moderate cytotoxicity evidenced in the colorectal carcinoma (Caco-2) and colon carcinoma (HT-29) cells was attributed to apoptosis induction by selenium, as confirmed by acridine orange/ethidium bromide staining. Selenium uptake studies corroborated the transfection results, where significant transgene expression was evident for the overexpressed folate receptor-positive KB cells when compared to the other cells with less or no folate receptors.
Highlights
Advancements in cancer genetics have heralded a new era of gene therapeutics, with novel approaches in gene delivery designed to permanently or transiently change phenotypes currently being investigated [1]
The hydroxyl groups of chitosan reacted with SeO32−, which was reduced to selenium nanoparticles (SeNPs) by ascorbic acid [28]
The SeNPs were predominantly spherical in shape, as seen under transmission electron microscopy (TEM) (Figure 1), with an average size of 85.3 ± 8 nm and a negative zeta (ζ) potential (−14.8 ± −3.6 mV) (Table 1)
Summary
Advancements in cancer genetics have heralded a new era of gene therapeutics, with novel approaches in gene delivery designed to permanently or transiently change phenotypes currently being investigated [1]. Gene therapy holds promise for the treatment of many genetic diseases and has primarily focused on plasmid DNA (pDNA) and small interfering RNA (siRNA). Nanoparticle-mediated mRNA transfection favours the combination of different therapeutic mRNAs on one carrier, allowing for adjustment by changing the amount and type of mRNA transfected. Despite these advantages over DNA, delivery of mRNA as a gene therapeutic has only recently re-emerged as it was previously deemed too unstable to work with. Stability has been increased through several modification strategies to improve the feasibility of mRNA for in vitro and in vivo studies [7,8]
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