Modulating the Protein Corona on Nanoparticles by Finely Tuning Cross-Linkers Improves Macrophage Targeting in Oral Small Interfering RNA Delivery

IF 15.8 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

ACS Nano Pub Date : 2025-04-24 DOI:10.1021/acsnano.4c18033

Hengqing Liu, Shengqi Li, Xin Yu, Qian Xu, Cui Tang, Chunhua Yin

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Abstract

The protein corona (PC) plays an important role in regulating the in vivo fate of nanoparticles (NPs). Modulating the surface chemical properties of NPs to control PC formation provides an alternative impetus for the oral delivery of small interfering RNA (siRNA). Herein, using tripolyphosphate (TPP), hyaluronic acid, and poly-γ-glutamic acid as cross-linkers, three types of mannose-modified trimethyl chitosan–cysteine (MTC)-based NPs with distinct surface chemistries were prepared to encapsulate siRNA via ionic gelation. The MTC-based NPs that were cross-linked exclusively with TPP (MTC/TPP/siRNA NPs) exhibited greater thiol group accessibility on their surfaces, resulting in a stronger affinity for apolipoprotein (APO) B48 during translocation across intestinal epithelia. Moreover, intracellular transport of MTC/TPP/siRNA NPs via the endoplasmic reticulum and Golgi apparatus further increased adsorption of APOB48, a key component of chylomicrons, which follow a similar transport pathway. Benefiting from the elevated APOB48 levels within the PC, the orally delivered MTC/TPP/siRNA NPs showed higher uptake by hepatic macrophages and better therapeutic efficacy for acute liver injury. Our results elucidate the role of NP surface chemical characteristics and translocation mechanisms across intestinal epithelia in forming oral PC, providing valuable insights for designing NPs that achieve effective oral gene delivery by customizing PC formation in vivo.

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通过微调交联剂调节纳米颗粒上的蛋白质电晕提高口服小干扰RNA递送中的巨噬细胞靶向性

蛋白质电晕（PC）在调节纳米颗粒（NPs）在体内的命运中起着重要的作用。通过调节NPs的表面化学性质来控制PC的形成，为小干扰RNA （siRNA）的口服递送提供了另一种动力。本研究以三聚磷酸酯（TPP）、透明质酸和聚γ-谷氨酸为交联剂，制备了三种表面化学性质不同的甘露糖修饰三甲基壳聚糖半胱氨酸（MTC） NPs，通过离子凝胶封装siRNA。仅与TPP交联的基于MTC的NPs （MTC/TPP/siRNA NPs）在其表面表现出更大的硫醇基团可及性，从而在肠上皮易位过程中对载脂蛋白（APO） B48具有更强的亲和力。此外，MTC/TPP/siRNA NPs通过内质网和高尔基体在细胞内运输进一步增加了乳糜微粒的关键成分APOB48的吸附，它们遵循类似的运输途径。得益于PC内APOB48水平的升高，口服MTC/TPP/siRNA NPs被肝巨噬细胞吸收，对急性肝损伤的治疗效果更好。我们的研究结果阐明了NP表面化学特征和跨肠上皮易位机制在口腔PC形成中的作用，为设计通过定制体内PC形成实现有效口服基因传递的NP提供了有价值的见解。

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来源期刊

ACS Nano 工程技术-材料科学：综合

CiteScore

26.00

自引率

4.10%

发文量

1627

审稿时长

1.7 months

期刊介绍： ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.