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Updated: Mar 28, 2026
Investigating Target Gene Function in a CD40 Agonistic Antibody-induced Colitis Model using CRISPR/Cas9-based Technologies
Published on: June 2, 2021
Colonic gene silencing using siRNA-loaded calcium phosphate/PLGA nanoparticles ameliorates intestinal inflammation in
Annika Frede1, Bernhard Neuhaus2, Robert Klopfleisch3
1Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Germany; Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Abstract:
Cytokines and chemokines are predominant players in the progression of inflammatory bowel diseases. While systemic neutralization of these players with antibodies works well in some patients, serious contraindications and side effects have been reported. Therefore, the local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach. In this study, we produced multi-shell nanoparticles consisting of a calcium phosphate (CaP) core coated with siRNA directed against pro-inflammatory mediators, encapsulated into poly(d,l-lactide-co-glycolide acid) (PLGA), and coated with a final outer layer of polyethyleneimine (PEI), for the local therapeutic treatment of colonic inflammation. In cell culture, siRNA-loaded CaP/PLGA nanoparticles exhibited a rapid cellular uptake, almost no toxicity, and an excellent in vitro gene silencing efficiency. Importantly, intrarectal application of these nanoparticles loaded with siRNA directed against TNF-α, KC or IP-10 to mice suffering from dextran sulfate sodium (DSS)-induced colonic inflammation led to a significant decrease of the target genes in colonic biopsies and mesenteric lymph nodes which was accompanied with a distinct amelioration of intestinal inflammation. Thus, this study provides evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of intestinal inflammation.
Insights
Novel nanoparticles deliver siRNA locally to reduce inflammation in the colon. This targeted approach shows promise for treating inflammatory bowel diseases with fewer side effects than systemic treatments.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Gastroenterology
Background:
- Cytokines and chemokines drive inflammatory bowel diseases (IBD).
- Systemic antibody treatments for IBD have significant side effects.
- Local therapeutic strategies are needed for IBD treatment.
Purpose of the Study:
- To develop and evaluate siRNA-loaded nanoparticles for local treatment of colonic inflammation.
- To assess the efficacy of nanoparticles in reducing pro-inflammatory gene expression in vivo.
- To investigate the therapeutic potential of targeted nanoparticle delivery for IBD.
Main Methods:
- Fabrication of multi-shell nanoparticles with a calcium phosphate (CaP) core, siRNA, poly(d,l-lactide-co-glycolide acid) (PLGA), and polyethyleneimine (PEI).
- In vitro assessment of nanoparticle cellular uptake, toxicity, and gene silencing efficiency.
- In vivo intrarectal administration of nanoparticles in a dextran sulfate sodium (DSS)-induced mouse model of colitis.
Main Results:
- CaP/PLGA nanoparticles demonstrated rapid cellular uptake and minimal toxicity in vitro.
- High in vitro gene silencing efficiency against pro-inflammatory mediators.
- Significant reduction in target genes (TNF-α, KC, IP-10) in colonic tissue and lymph nodes of treated mice.
- Distinct amelioration of intestinal inflammation following nanoparticle treatment.
Conclusions:
- CaP/PLGA nanoparticles effectively deliver siRNA for local gene silencing in the colon.
- Nanoparticle-mediated siRNA delivery significantly reduces inflammation in a DSS-induced colitis model.
- This approach offers a promising strategy for targeted IBD therapy with potential for reduced systemic side effects.
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