A Molecular Targeted Immunotherapeutic Strategy for Ulcerative Colitis via Dual-targeting Nanoparticles Delivering miR-146b to Intestinal Macrophages

• Published in: Journal of Crohn's and colitis 2019-03, Vol.13 (4), p.482-494
• Main Authors: Deng, Feihong, He, Shuying, Cui, Shudan, Shi, Yanqiang, Tan, Yuyong, Li, Zhijun, Huang, Chongyang, Liu, Deliang, Zhi, Fachao, Peng, Liang
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Body Weight - drug effects; Carcinogenesis - drug effects; Cell Proliferation - drug effects; Colitis - chemically induced; Colitis - drug therapy; Colitis - pathology; Colitis - prevention & control; Colitis, Ulcerative - drug therapy; Dextran Sulfate; Disease Models, Animal; Immunotherapy - methods; Interleukin-10 - metabolism; Intestinal Mucosa - immunology; Intestinal Mucosa - physiopathology; Macrophage Activation - drug effects; Macrophages - physiology; Male; Mice; MicroRNAs - administration & dosage; MicroRNAs - genetics; MicroRNAs - therapeutic use; Molecular Targeted Therapy - methods; Nanoparticles - therapeutic use; Phenotype; Regeneration - drug effects; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Toll-Like Receptor 4 - antagonists & inhibitors
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjy181

Abstract Background and Aims Macrophages are a promising therapeutic target for intestinal mucosal repair. MiR-146b appears to control macrophage activation and cell proliferation. Methods By loading miR-146b mimic on mannose-modified trimethyl chitosan [MTC]-conjugated nanoparticles [NPs] [MTC-miR146b], a molecular targeted immunotherapeutic approach was developed to selectively target intestinal macrophages for mucosal regeneration and tumourigenesis in mouse models. Results We first confirmed that miR-146b expression was significantly enhanced during mucosal regeneration in a murine colitis model. Moreover， after mucosal damage, MTC-miR146b mimic-treated wild-type mice had dramatically restored body weight and mucosal barrier function compared with MTC-NC treated mice. Strikingly, MTC-miR146b mimic oral administration protected miR-146b-deficient mice from dextran sodium sulphate [DSS] injury and the colitis-associated cancer process. Mechanistically, miR-146b strongly inhibited M1 macrophage activation by suppressing the Toll-like receptor 4 [TLR4] signalling pathway, resulting in the repression of the induction of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. More importantly, miR-146b overexpression in bone marrow-derived macrophages [BMDMs] in M1 differentiation conditions induced a phenotype similar to M2 macrophages and improved the proliferation of co-cultured colonic epithelial cells via STAT3-dependent IL-10 production. Conclusions MTC-miR146b should be regarded as an effective candidate for oral delivery and could improve the efficacy of immunotherapies for ulcerative colitis and colitis-associated cancer.