Nanoparticle (NP) drug delivery systems have been successfully designed and implemented to orally deliver siRNAs for inflammatory disorders. However, the influence of surface charge on orally administered siRNA nanocarriers has not been investigated. In this study, we prepared structurally related poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) (PEG_5K-b-PLGA_10K) NPs with the assistance of a synthesized lipid featuring surface amine groups for subsequent charge tuning. NPs were prepared by a double emulsion method, and their surface charge could be tuned and controlled by a succinylation reaction to yield NPs with different surface charges, while maintaining their size and composition. The prepared NPs were termed as aminated NPs (ANPs), plain NPs (PNPs), or carboxylated NPs (CNPs) based on their surface charge. All NPs exhibited the desired structural stability and siRNA integrity after enzymatic degradation. In vivo studies showed that ANPs significantly accumulated in inflamed colons, and they were successful in decreasing TNF-α secretion and mRNA expression levels while maintaining colonic histology in a murine model of acute ulcerative colitis (UC). This study described a methodology to modify the surface charge of siRNA-encapsulating polymeric NPs and highlighted the influence of surface charge on oral delivery of siRNA for localized inflammatory disorders.

中文翻译：

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用于TNF-αsiRNA口服递送的表面电荷可调纳米颗粒，用于治疗溃疡性结肠炎

纳米颗粒（NP）药物递送系统已经成功设计和实现，可口服递送用于炎症性疾病的siRNA。然而，尚未研究表面电荷对口服给予的siRNA纳米载体的影响。在这项研究中，我们制备了结构相关的聚乙二醇-嵌段-聚乳酸-乙醇酸共聚物（PEG _5K - b -PLGA _10K）NPs具有表面胺基团的合成脂质的辅助，用于随后的电荷调节。通过双乳化法制备NP，可以通过琥珀酰化反应调节和控制其表面电荷，以产生具有不同表面电荷的NP，同时保持其大小和组成。根据其表面电荷，制备的NP称为胺化NP（ANP），纯NP（PNP）或羧化NP（CNP）。酶降解后，所有NPs均显示出所需的结构稳定性和siRNA完整性。体内研究表明，在急性溃疡性结肠炎（UC）的鼠模型中，ANPs在发炎的结肠中大量积聚，并且在降低TNF-α分泌和mRNA表达水平的同时，还能维持结肠组织学。