The endosomal entrapment of functional nanoparticles is a severe limitation to their use for biomedical applications. In the case of magnetic nanoparticles (MNPs), this entrapment leads to poor heating efficiency for magnetic hyperthermia and suppresses the possibility to manipulate them in the cytosol. Current strategies to limit their entrapment include functionalization with cell-penetrating peptides to promote translocation directly across the cell membrane or facilitate endosomal escape. However, these strategies suffer from the potential release of free peptides in the cell, and to the best of our knowledge, there is currently a lack of effective methods for the cytosolic delivery of MNPs after incubation with cells. Herein, we report the conjugation of fluorescently labeled cationic peptides to γ-Fe₂O₃@SiO₂ core-shell nanoparticles by click chemistry to improve MNP access to the cytosol. We compare the effect of Arg₉ and His₄ peptides. On the one hand, Arg₉ is a classical cell-penetrating peptide able to enter cells by direct translocation, and on the other hand, it has been demonstrated that sequences rich in histidine residues can promote endosomal escape, possibly by the proton sponge effect. The methodology developed here allows a high colocalization of the peptides and core-shell nanoparticles in cells and confirms that grafting peptides rich in histidine residues onto nanoparticles promotes NPs' access to the cytosol. Endosomal escape was confirmed by a calcein leakage assay and by ultrastructural analysis in transmission electron microscopy. No toxicity was observed for the peptide-nanoparticles conjugates. We also show that our conjugation strategy is compatible with the addition of multiple substrates and can thus be used for the delivery of cytoplasm-targeted therapeutics.

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