Oral pH- and inflammation-targeted delivery system with biodegradable multi-layer core-shell nanocapsules for the treatment of ulcerative colitisLi, Zhou, Gu
et alNanoscale (2025)
Abstract: Most biologics require administration via parenteral routes; however, the pain and local allergic reaction brought about by injection usually lead to poor compliance, especially for chronic patients. Meanwhile, the oral delivery of biologics faces great challenges due to the complex physiological environment of the gastrointestinal tract. Herein, we developed a new formulation of multilayer core-shell nanocapsules composed of hyaluronan-modified silica nanocapsules, chitosan and alginate layers for the oral delivery of biologics. The mesencephalic astrocyte-derived neurotrophic factor (MANF) was selected as the model biologic for the treatment of ulcerative colitis (UC). MANF-loaded biodegradable silica (MBS) nanocapsules were first obtained simultaneously with the preparation. Then, MBS nanocapsules were surface-modified with hyaluronan (MBSH) for oral targeted delivery to the inflamed region via CD44-mediated endocytosis. To survive in the harsh gastrointestinal environment, MBSH was further modified using chitosan and alginate via polyelectrolyte interactions. With this delivery system, i.e., MBSH@CA, the cumulative release of MANF protein in the simulated gastric fluid (SGF) and simulated intestine fluid (SIF) was <10% of the total amount in MBSH@CA. Bio-distribution studies showed that the MBSH@CA nanocapsules were mainly distributed in the colon after 24 h treatment. Ex vivo imaging of the colons revealed a preferential accumulation of the MBSH@CA nanocapsules in the inflamed colons compared with the healthy colons. According to in vivo anti-inflammatory analysis, the oral MBSH@CA nanocapsules were effective in reducing related inflammatory symptoms caused by DSS-induced colitis. All of the above results suggested that the multilayer silica MBSH@CA nanocapsules could be employed for targeted drug delivery against UC.
Oral colon-targeted delivery of recombinant human MANF for alleviation of ulcerative colitisZhou, Li, Wei
et alInt J Pharm X (2025) 9, 100320
Abstract: Midbrain astrocyte-derived neurotrophic factor (MANF) is a secreted protein induced by endoplasmic reticulum stress. Previous studies have indicated that intravenous administration of 1 mg/kg/day recombinant human MANF protein with His tag (His-MANF) for 3 days can ameliorate acute ulcerative colitis in mice. However, long-term intravenous therapy has many disadvantages. In this paper, His-MANF protein was successfully encapsulated into alginate and hyaluronic acid hybrid hydrogel microcapsules in one step using the gas shear method and then coated by Eudragit S100 to construct an oral colon-targeted delivery system (MSH@E). The MSH@E microcapsules exhibited controlled and sustained release behavior and colon-targeting properties. Both fluorescent imaging and immunohistochemistry staining results showed that His-MANF protein could accumulate in the colitis colon for a longer residence time after oral delivery. In vivo studies demonstrated that oral administration of MSH@E microcapsules could alleviate DSS-induced colitis in mice without systemic toxicity. Importantly, even if the oral His-MANF dose was half of the intravenous His-MANF dose, oral delivery was still much more effective than intravenous injection, suggesting the development of the oral colon-targeted delivery system (MSH@E) has great significance and makes a breakthrough from intravenous to oral administration for His-MANF treatment of ulcerative colitis (UC).© 2025 The Authors. Published by Elsevier B.V.
Mesencephalic astrocyte-derived neurotrophic factor upregulates CHOP and ATF6 in the rat retina with retinitis pigmentosaGao, Hu, Huang
et alOphthalmic Genet (2025)
Abstract: In the current work, we investigated the potential protective function of MANF against the degeneration of RP in S334ter-3 rats and the mechanism underlying these effects.The left eye of rat was injected with MANF, and the right eye injected PBS as a control. The levels of those ER stress associated proteins were determined by western blot analysis.First, those ER stress associated proteins were detected in S334ter-3 rats. Among these proteins, a decrease in the expression of PERK was only showed from PD 6 to PD 12. Surprisingly, a dramatic increase of ATF6 was induced by injection MANF. Then, the expression of ATF6 protein declined rapidly to the control eye. Furthermore, a remarkable increase in the expression of CHOP was examined at 6 h, which peaked at 12 h and maintained the level until 48 h. At the same time, CHOP was detected in Müller cells but not in photoreceptor; nevertheless, photoreceptor survival clearly improved. The increasing expressions of CHOP and ATF6 in SD rats were similar to the changes in S33ter-3 rats after injection MANF.These results indicate that MANF may play an important role in protecting photoreceptor degeneration in RP.
Myeloid-derived MANF ameliorates ethanol-induced liver injury by enhancing microRNA-223 expressionXie, Zhang, Yang
et alJ Gastroenterol (2025)
Abstract: Myeloid cells play a pivotal role in the pathogenesis of alcoholic liver disease (ALD), yet the mechanisms regulating their function and specific contributions to ALD remain inadequately understood. This study aims to investigate the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in the development of ALD.Myeloid-specific Manf knockout mice and wild-type controls were fed an ethanol-based diet for 10 days, followed by a single ethanol binge. Hepatic MANF levels, along with the correlation between MANF and inflammatory factors in patients with alcoholic hepatitis, were analyzed using the GSE28619 dataset.Our study demonstrated that myeloid MANF expression in the liver was upregulated following chronic-plus-binge ethanol exposure. Deletion of the Manf gene in myeloid cells, including neutrophils, exacerbated ethanol-induced liver injury, steatosis, neutrophil infiltration, and reactive oxygen species production. Mechanistic analysis revealed that MANF promotes neutrophil miR-223 expression, a key anti-inflammatory factor in these cells. MANF enhances miR-223 transcription by increasing the expression of the transcription factor PU.1 via p38 mitogen-activated protein kinase signaling. In addition, hepatic MANF levels were elevated in patients with alcoholic hepatitis and correlated with IL-6, IL-1β, and phagocytic oxidase (phox) p47phoxlevels.Myeloid-derived MANF mitigates alcohol-induced liver injury by upregulating the neutrophilic p38-PU.1-miR-223 axis.© 2025. The Author(s), under exclusive licence to Japanese Society of Gastroenterology.
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