title: Optimization of multifunctional chitosan-siRNA nanoparticles for oral delivery applications, targeting TNF-α silencing in rats.
abstract: Secretion of tumor necrosis factor-α (TNF-α) by macrophages plays a predominant role in the development and progression of various inflammatory diseases. In the current contribution, multifunctional nanoparticles (NPs) containing TNF-α siRNA targeting macrophages via oral administration were developed to knockdown TNF-α expression against acute hepatic injury in rats. Mannose-modified trimethyl chitosan-cysteine (MTC) NPs were prepared by self-assembly method (sa-MTC NPs), ionic gelation and siRNA entrapment method (en-MTC NPs), and ionic gelation and siRNA adsorption method (ad-MTC NPs). Among them, en-MTC NPs demonstrated the best stability against ionic challenges with desired siRNA integrity against nucleases. By targeting normal enterocytes and M cells that express mannose receptors, en-MTC NPs notably promoted intestinal absorption of siRNA in rats. They further facilitated siRNA internalization by rat peritoneal exudate cells (PECs) via lipid-raft involved endocytosis and macropinocytosis, thus inducing effective in vitro TNF-α knockdown. Orally delivered en-MTC NPs at a low siRNA dose of 50 μg/kg inhibited systemic TNF-α production and decreased TNF-α mRNA levels in macrophage-enriched liver, spleen, and lung tissues, which consequently protected rats from acute hepatic injury. Therefore, the en-MTC NPs would provide an effective approach to orally deliver TNF-α siRNA for the anti-inflammatory therapy.
authors: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors: Chunbai
authors: C
authors: He
authors: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors: Lichen
authors: L
authors: Yin
authors: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors: Yudong
authors: Y
authors: Song
authors: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors: Cui
authors: C
authors: Tang
authors: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China. Electronic address: chyin@fudan.edu.cn.
authors: Chunhua
authors: C
authors: Yin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D048271:Chitosan / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry; D016503:Drug Delivery Systems; D004705:Endocytosis; D020868:Gene Silencing; D007249:Inflammation / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000293:injuries; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008358:Mannose / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D048271:Chitosan; D003545:Cysteine; D008358:Mannose
keywords: Anti-inflammation; Multifunctional nanoparticles; Oral delivery; RNA interference; TNF-α siRNA