Oligo-His 肽与磁性 γ-Fe2O3@SiO2 核壳纳米粒子的共轭促进其进入细胞质,ACS Applied Materials & Interfaces

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Oligo-His 肽与磁性 γ-Fe2O3@SiO2 核壳纳米粒子的共轭促进其进入细胞质
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2022-03-23 , DOI: 10.1021/acsami.2c01346
Mathilde Le Jeune _{1,

2} , Emilie Secret ₁ , Michaël Trichet ₃ , Aude Michel ₁ , Delphine Ravault ₂ , Françoise Illien ₂ , Jean-Michel Siaugue ₁ , Sandrine Sagan ₂ , Fabienne Burlina ₂ , Christine Ménager ₁

Affiliation

功能性纳米粒子的内体截留严重限制了它们在生物医学应用中的应用。在磁性纳米粒子 (MNP) 的情况下，这种包埋导致磁热疗的加热效率较差，并抑制了在胞质溶胶中对其进行操作的可能性。目前限制它们被困的策略包括用细胞穿透肽进行功能化，以促进直接穿过细胞膜的易位或促进内体逃逸。然而，这些策略受到细胞中游离肽的潜在释放的影响，据我们所知，目前缺乏与细胞孵育后 MNPs 胞浆递送的有效方法。在此，我们报道了荧光标记的阳离子肽与 γ-Fe ₂ O的结合。₃ @SiO ₂核-壳纳米粒子通过点击化学改善 MNP 进入细胞质。我们比较了 Arg ₉和 His ₄肽的效果。一方面，Arg ₉是一种经典的细胞穿透肽，能够通过直接易位进入细胞，另一方面，已经证明富含组氨酸残基的序列可以促进内体逃逸，可能是通过质子海绵效应。这里开发的方法允许肽和核壳纳米颗粒在细胞中的高度共定位，并证实将富含组氨酸残基的肽移植到纳米颗粒上可以促进 NP 进入细胞质。通过钙黄绿素渗漏测定和透射电子显微镜中的超微结构分析证实了内体逃逸。没有观察到肽-纳米颗粒缀合物的毒性。我们还表明，我们的缀合策略与添加多种底物兼容，因此可用于递送细胞质靶向治疗剂。

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Conjugation of Oligo-His Peptides to Magnetic γ-Fe2O3@SiO2 Core–Shell Nanoparticles Promotes Their Access to the Cytosol

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.

更新日期：2022-03-23

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