Abstract
BackgroundIn recent years, the use of ferritins as nano-vehicles for drug delivery is taking center stage. Compared to other similar nanocarriers, Archaeoglobus fulgidus ferritin is particularly interesting due to its unique ability to assemble-disassemble under very mild conditions. Recently this ferritin was engineered to get a chimeric protein targeted to human CD71 receptor, typically overexpressed in cancer cells.ResultsArchaeoglobus fulgidus chimeric ferritin was used to generate a self-assembling hybrid nanoparticle hosting an aminic dendrimer together with a small nucleic acid. The positively charged dendrimer can indeed establish electrostatic interactions with the chimeric ferritin internal surface, allowing the formation of a protein-dendrimer binary system. The 4 large triangular openings on the ferritin shell represent a gate for negatively charged small RNAs, which access the internal cavity attracted by the dense positive charge of the dendrimer. This ternary protein-dendrimer-RNA system is efficiently uptaken by acute myeloid leukemia cells, typically difficult to transfect. As a proof of concept, we used a microRNA whose cellular delivery and induced phenotypic effects can be easily detected. In this article we have demonstrated that this hybrid nanoparticle successfully delivers a pre-miRNA to leukemia cells. Once delivered, the nucleic acid is released into the cytosol and processed to mature miRNA, thus eliciting phenotypic effects and morphological changes similar to the initial stages of granulocyte differentiation.ConclusionThe results here presented pave the way for the design of a new family of protein-based transfecting agents that can specifically target a wide range of diseased cells.Graphic abstract
Highlights
The development of nanosystems for drug delivery is a fast-expanding area in scientific research, especially in the field of tumor treatment [1,2,3,4,5,6,7,8]
We have developed a self-assembling molecular matryoshka in which ferritin traps a positively charged polyamine dendrimer (Poly(amidoamine) or PAMAM) that acts as an anion sponge for negatively charged molecules, nucleic acids in particular
In the hybrid nanosystem we have developed, the PAMAM is protected within the ferritin cavity, and this prevents the direct interaction of the dendrimer with the membrane, which is typically crucial for its rupture
Summary
Archaeoglobus fulgidus chimeric ferritin was used to generate a self-assembling hybrid nanoparticle hosting an aminic dendrimer together with a small nucleic acid. The 4 large triangular openings on the ferritin shell represent a gate for negatively charged small RNAs, which access the internal cavity attracted by the dense positive charge of the dendrimer. This ternary protein-dendrimerRNA system is efficiently uptaken by acute myeloid leukemia cells, typically difficult to transfect. The nucleic acid is released into the cytosol and processed to mature miRNA, eliciting phenotypic effects and morphological changes similar to the initial stages of granulocyte differentiation
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