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RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Although administering small interfering RNA (siRNA) via an oral route is desirable, various hurdles including physicochemical, mucus, and cellular uptake barriers of the gastrointestinal tract (GIT) impede both the delivery of siRNA...
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... gastrointestinal conditions, intestinal barrier (both mucus and inflamed epithelium) penetration issues, cell-targeting ability, and intracellular penetration are significant issues for the successful inflamed tissue/cell-specific delivery of siRNA-loaded drug delivery systems compared to conventional oral drug delivery formulations that usually exploit pH variances, transit time differences, and gut microbiome variations between the stomach, small intestine, and large intestine [44]. The details of each obstacle and strategies to overcome them will be discussed in the following sections (Table 1 and Figure 1). Lipo-polyplex embedded in hydrogels or polymeric materials --Increases the stability of loaded siRNA drugs in the harsh environment by providing an additional protective layer hamper efficient release of loaded materials from the embedding materials. ...Context 2
... the successful treatment of disease by oral delivery, the system needs to overcome major biochemical barriers such as enzymatic degradation (Table 1 and Figure 1a). In the stomach environment, digestive enzymes such as pepsin and gelatinase can degrade biological therapeutics. ...Context 3
... avoid degradation by nucleases, orally administered nucleic acid-based drugs have been either chemically modified to improve stability against enzymes or incorporated into nanocarrier systems to shield against enzymatic attacks (Table 1 and Figure 1a). The chemical modification of siRNA drugs is typically based on internucleotide linkage, nucleobase, or sugar modification. ...Context 4
... most cases, siRNA drugs are rapidly excreted due to a lack of inherent targeting ability and small size. Thus, other strategies including nanomedicine-based protection have gained much attention from siRNA researchers because of various advantages, including enhanced targeting ability and the improvement of half-life [26] (Table 1 and Figure 1a). Another advantage of nanoparticle-based strategies is the enhanced intracellular delivery of siRNA, although this is not guaranteed by the above strategies. ...Context 5
... strategies based on lipoplexes, polyplexes, or PEGylation are common for the specific penetration of the thin or denuded mucus of the inflamed gut. However, utilizing mucolytic agents is not a good option because the non-specific removal of the mucus layer affects the non-specific accumulation of nanoparticles into healthy tissue, and the non-restricted passage of pathogens and other molecules could occur (Table 1 and Figure 1b). ...Context 6
... phenomenon usually affects unregulated mucosal immune responses against gut microbiota. Thus, orally administered nano-based drug carriers could accumulate in the inflamed sites via both the denuded mucus layer and the disrupted Pharmaceutics 2022Pharmaceutics , 14, 1969 7 of 21 intestinal epithelium (Table 1 and Figure 1b). In contrast, the carriers are rarely localized in the healthy gut due to the intact mucus layer and tight intestinal epithelium [72]. ...Context 7
... leads to the specific delivery of oral nanomedicines to inflamed tissue [72]. The further functionalization of targeting ligands on the nanoparticles could improve drug targeting to the sites [72] (Table 1 and Figure 1b). Targeting intestinal epithelium and macrophages is a common active targeting strategy. ...Context 8
... effective siRNA drug penetration through cellular membranes, the most challenging barrier is a high density of negative charges on the target cells such as intestinal epithelium cells and immune cells [26,83]. The cellular membrane is typically composed of negatively charged phospholipids in a bilayer, which disrupt siRNA intracellular delivery due to repulsive interactions between the negative charges of both siRNA and cellular membranes [26,83] ( Figure 1c and Table 1). ...Context 9
... or polyplexes formed between nucleic acid-based therapeutics and cationic lipids or polymers could fuse with cellular membranes due to increased lipophilicity, leading to enhanced intracellular uptake. The final fate of the lipoplex or polyplex depends on the net charge of the complex (Table 1 and Figure 1c). A strong negative net charge of the lipoplex or polyplex could hinder the intracellular uptake of the nanoparticles from charge-charge repulsion, although lipophilicity is increased [44]. ...Context 10
... comparison, active targeting functionalized nanoparticles are taken up by specific cell types such as inflamed epithelial and activated macrophages (please see the previous part for the targeting ligand counterparts) [4]. In these cases, a cationic net charge is not necessary because intracellular uptake can occur via receptormediated endocytosis (Table 1). When reaching target sites, nanoparticles without the functionalization of targeting ligands could be non-specifically internalized into many kinds of cells after the penetration of the mucus layers. ...Context 11
... comparison, active targeting functionalized nanoparticles are taken up by specific cell types such as inflamed epithelial and activated macrophages (please see the previous part for the targeting ligand counterparts) [4]. In these cases, a cationic net charge is not necessary because intracellular uptake can occur via receptor-mediated endocytosis (Table 1). ...Similar publications
RNA interference based therapeutic gene silencing is an emerging platform for managing highly metastatic breast cancer. Cytosolic delivery of functional siRNA remains the key obstacle for efficient RNAi therapy. To overcome the challenges of siRNA delivery, we have engineered a vitamin E-tethered, short, optimum protease stabilized facial lipopepti...
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Inflammatory bowel disease (IBD) is an idiopathic chronic inflammatory bowel disease with high morbidity and an increased risk of cancer or death, resulting in a heavy societal medical burden. While current treatment modalities have been successful in achieving long-term remission and reducing the risk of complications, IBD remains incurable. Nanomedicine has the potential to address the high toxic side effects and low efficacy in IBD treatment. However, synthesized nanomedicines typically exhibit some degree of immune rejection, off-target effects, and a poor ability to cross biological barriers, limiting the development of clinical applications. The emergence of bionic materials and bionic technologies has reshaped the landscape in novel pharmaceutical fields. Biomimetic drug-delivery systems can effectively improve biocompatibility and reduce immunogenicity. Some bioinspired strategies can mimic specific components, targets or immune mechanisms in pathological processes to produce targeting effects for precise disease control. This article highlights recent research on bioinspired and biomimetic strategies for the treatment of IBD and discusses the challenges and future directions in the field to advance the treatment of IBD.
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with a complex and multifactorial etiology, making it challenging to treat. While recent advances in immunomodulatory biologics, such as antitumor necrosis factor-α (TNF-α) antibodies, have shown moderate success, systemic administration of antibody therapeutics may lead to several adverse effects, including the risk of autoimmune disorders due to systemic cytokine depletion. Transient RNA interference using exogenous short interfering RNA (siRNA) to regulate target gene expression at the transcript level offers an alternative to systemic immunomodulation. However, siRNAs are susceptible to premature degradation and have poor cellular uptake. Graphene oxide (GO) nanoparticles have been shown to be effective nanocarriers for biologics due to their reduced cytotoxicity and enhanced bioavailability. In this study, we evaluate the therapeutic efficacy of GO mediated TNF-α_siRNA using in vitro models of chronic inflammation generated by treating murine small intestines (enteroids) and large intestines (colonoids) with inflammatory agents IL-1β, TNF-α, and LPS. The organotypic mouse enteroids and colonoids developed an inflammatory phenotype similar to that of IBD, characterized by impaired epithelial homeostasis and an increased production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. We assessed siRNA delivery to these inflamed organoids using three different GO formulations. Out of the three, small-sized GO with polymer and dendrimer modifications (smGO) demonstrated the highest transfection efficiency, which led to the downregulation of inflammatory cytokines, indicating an attenuation of the inflammatory phenotype. Moreover, the transfection efficiency and inflammation-ameliorating effects could be further enhanced by increasing the TNF-α_siRNA/smGO ratio from 1:1 to 3:1. Overall, the results of this study demonstrate that ex vivo organoids with disease-specific phenotypes are invaluable models for assessing the therapeutic potential of nanocarrier-mediated drug and biologic delivery systems.
The human intestinal epithelium has an impressive ability to respond to insults and its homeostasis is maintained by well-regulated mechanisms under various pathophysiological conditions. Nonetheless, acute injury and inhibited regeneration of the intestinal epithelium occur commonly in critically ill surgical patients, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Effective therapies for the preservation of intestinal epithelial integrity and for the prevention of mucosal hemorrhage and gut barrier dysfunction are limited, primarily because of a poor understanding of the mechanisms underlying mucosal disruption. Noncoding RNAs (ncRNAs), which include microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and small vault RNAs (vtRNAs), modulate a wide array of biological functions and have been identified as orchestrators of intestinal epithelial homeostasis. Here, we feature the roles of many important ncRNAs in controlling intestinal mucosal growth, barrier function, and repair after injury-particularly in the context of postoperative recovery from bowel surgery. We review recent literature surrounding the relationships between lncRNAs, microRNAs, and RNA-binding proteins and how their interactions impact cell survival, proliferation, migration, and cell-to-cell interactions in the intestinal epithelium. With advancing knowledge of ncRNA biology and growing recognition of the importance of ncRNAs in maintaining the intestinal epithelial integrity, ncRNAs provide novel therapeutic targets for treatments to preserve the gut epithelium in individuals suffering from critical surgical disorders.
Background & aims: Inflammatory bowel disease (IBD) is a condition characterized by chronic inflammation of the gastrointestinal tract, manifesting as either Crohn's disease (CrD) or ulcerative colitis (UC). Current treatment options for CrD and UC primarily focus on symptom management. In recent years, advancements in nanotechnology have increased the clinical applicability of nanoparticles (NPs) in treating IBD. This review explores the current research on NP-mediated drug-delivery systems for IBD treatment and assesses its advantages and limitations. Results: The authors examine diverse nanomedicine applications for IBD and address the current challenges and prospects in the field to advance nanomediated therapies in the future. Conclusion: Innovative NP-based treatment strategies promise a reliable and effective approach to IBD management.
Small interfering RNA (siRNA)drugs have great potential in the field of anti-tumor, but they have poor biological stability and are easily degraded by nucleases in vivo, resulting in poor bioavailability. In this study, a novel albumin Poly(lactide-co-glycolide) (PLGA) nanocarrier was prepared to efficiently deliver siRNA to glioma cells to achieve tumor-targeted therapy. Recombinant VAR2CSA protein (RVP) targeting albumin PLGA nanocarriers (RVP–APN–siRNA) loaded with EGFR-siRNA were prepared by a double emulsion method. Determine its characterization performance, loading rate, in vitro release and cell uptake, and investigate the effects of nanoparticles on the cytotoxicity, proliferation and apoptosis of brain glioma cells. The prepared nanoparticles are spherical with uniform particle size, the average particle size distribution is 120–180 nm, the average potential distribution is 20–30 mv, and the loading rate is 82.36 ± 1.84%. The release rate of siRNA within 24 h is 93%, with low cytotoxicity and targeting performance, effectively inhibiting the activity of glioma cells. The prepared albumin nanoparticles have good physical and chemical properties, and have dual functions of targeted recognition of glioma cells and tumor treatment. They are efficient and safe nano-carriers for tumor-targeted treatment, and have good potential in the application of siRNA-targeted drug delivery.
Inflammatory bowel disease is known to be associated with alterations in gut microbiota. The bioactive compound syringic acid has been shown to alleviate inflammatory bowel disease, but its interaction with gut microbiota and mechanism of action remain unclear. To address this, we conducted a study in which we investigated the potential benefits of syringic acid in a mouse model of dextran sulfate sodium-induced colitis through gut microbiota modulation. Our results show that oral administration of syringic acid effectively reduced symptoms of colitis, as indicated by reduced disease activity index, and histopathology scores. Moreover, syringic acid administration enriched the abundance of Alistipes and norank_f__norank_o__Gastranaerophilales in mice, suggesting a restoration of impaired gut microbiota. Notably, we found that the effects of syringic acid were similar to those of fecal microbiota transplantation in dextran sulfate sodium-induced mice. Further analysis revealed that syringic acid inhibited the NLRP3-Cas-1-GSDMD-IL-1β inflammatory vesicle signaling pathway, leading to amelioration of colonic inflammation in a gut microbiota-dependent manner. Our findings demonstrate the potential of syringic acid as a preventive and therapeutic agent for inflammatory bowel disease.
