Multifunctional magnetite nanoparticles to enable delivery of siRNA for the potential treatment of Alzheimer’s

Abstract

Therapeutic drugs for Alzheimer’s disease have been extensively studied due to its recurrence and abundance among neurodegenerative diseases. It is thought that the accumulation of amyloid precursor protein (APP) products, a consequence of an up-regulation of the β-site APP-cleaving enzyme 1 (BACE1), is the main triggering mechanism during the early stages of the disease. This study aims to explore the ability of a multifunctional conjugate based on magnetite nanoparticles for the cellular delivery of siRNA against the expression of the BACE1 gene. We immobilized the siRNA strand on PEGylated magnetite nanoparticles and investigated the effects on biocompatibility and efficacy of the conjugation. Similarly, we co-immobilized the translocating protein OmpA on PEGylated nanoparticles to enhance cellular uptake and endosomal escape. BACE1 suppression was statistically significant in HFF-1 cells, without any presence of a cytotoxic effect. The delivery of the nanoconjugate was achieved through endocytosis pathways, where endosome formation was likely escaped due to the proton-sponge effect characteristic of PEGylated nanoparticles or mainly by direct translocation in the case of OmpA/PEGylated nanoparticles.

Magnetite Nanoparticles Functionalized with RNases against Intracellular Infection of Pseudomonas aeruginosa

“…Figure 7 B exemplifies how large nanobioconjugate clusters can be also internalized and accumulate without altering cell morphology. We believe that the pendant groups of PEA facilitate cell penetration, as has been previously described by us and others [ 33 , 79 ]. In particular, the intermingling with glycosaminoglycans and phospholipids in the membrane appear to be involved in bypassing the bilayer [ 80 ].…”

“…Moreover, it has been reported that native RNase 3 tends to accumulate in the specialized primary lysosomes of eosinophil cells, which provides further evidence of the tendency of our MNPs-RNase 3/1 nanobioconjugates to remain trapped in the lysosomal compartments of macrophages [78]. In contrast, other studies conducted by our research group demonstrated that functionalized MNPs without immobilized protein have lower colocalization with lysosomal compartments in comparison to MNPs-RNases [79]. Figure 7B exemplifies how large nanobioconjugate clusters can be also internalized and accumulate without altering cell morphology.…”

Patchy Core/Shell, Magnetite/Silver Nanoparticles via Green and Facile Synthesis: Routes to Assure Biocompatibility

“…The nanomaterials capable of withholding different chemistries on their surfaces, such as antibodies, small interfering RNA (siRNA), or peptides, are of great interest, particularly in the medical field [ 39 , 40 ]. In our case, we are interested in the conjugation of translocating peptides and proteins for efficient cell penetration and endosomal escape.…”

Tailoring Iron Oxide Nanoparticles for Efficient Cellular Internalization and Endosomal Escape

“…Recently, we also designed multifunctional orthopyridyl disulfide-PEG succimidyl ester (OPSS-PEG-NHS) coated IONs to enable the delivery of siRNA for silencing the BACE1 gene expression, as potential treatment of Alzheimer’s disease. The immobilization of OmpA on the surface of these PEGylated IONs increased their endosomal escape efficiency in neuroblastoma cells from 68% to 88%, demonstrating the potent escape abilities of this protein [ 269 ].…”

“…Hybrid ION/UCNP systems have been widely applied in cancer therapy, MRI and diagnosis, gene therapy, and drug delivery [ 308 ]. In general, the most prevalent host matrices for iron oxide core-shell nanoparticles include Y 2 O 3 , Y 2 O 2 S, LaF 3 , BaYF 5 , NaYF 4 , and NaGdF 4 , which have been doped with Yb 3+ /Tm 3+ and Yb 3+ /Er 3+ ions [ 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , …”