# Recent Advances in Nanoparticle-Mediated Treatment of Inflammatory Bowel Diseases
## 3 Chitosan-Alginate Nanoparticles  
Resident intestinal macrophages are key factors in the maintenance of intestinal homeostasis. Macrophage activation as well as cell proliferation is achieved by MiR-146b. Chitosan has chemical functional groups that can be modified to achieve specific goals and has been used as a carrier in polymeric nanoparticles for drug delivery, ensuring a positive surface charge and mucoadhesive properties. In their study, [PERSON] et al. used chitosan conjugation strategies and loaded miR-146b mimic on mannose-modified trimethyl chitosan-conjugated nanoparticles (MTC-miR146b) administered in mouse models for immunotherapy [10].  
Higher miR-146b expression was observed in the murine colitis model following mucosal recovery. The authors also noted improved mucosal barrier function and body weight status following mucosal injury in wild-type mice treated with MTC-miR146b as compared with mice treated with MTC-NC. When administered orally, MTC-miR146b offered protection against DSS inducing intestinal inflammation and colon cancer preceded by clinically detectable colitis (CAC) in miR-146b knockout mice. Through the firm suppression of the signaling pathway of toll-like receptor 4, miR-146b could inhibit the activation of M1 macrophages in a mechanistic manner and repressed the induction of pro-inflammatory cytokines (TNF-\(\alpha\), IL-6 and IL-1\(\beta\)). Differentiated M1 cells bring about the over-expression of miR-146b in bone marrow-derived macrophages determining an M2-like phenotype. In addition, the proliferation rate of intestinal epithelial cells that were co-cultured was significantly affected through an IL-10/STAT3 dependent mechanism.  
According to [PERSON] et al., the oral administration of MTC-miR146b was efficient and it could improve the efficacy of immunotherapy in patients with UC and CAC [10].  
In another study, orally delivered CD98 siRNA was efficiently carried through the mucus and taken up by colon cells, the nanoparticles being able to escape from the endosomes/lysosomes. [11]. The authors designed single-chain CD98 antibody (scCD98)-PEG-urocanic acid (UAC)-modified chitosan (scCD98-PEG-UAC)/PEI (2 kilodalons)/siCD98 nanoparticles released from a hydrogel (chitosan and alginate) in order to avoid degradation in the GIT and achieve selective degradation at the site of inflammation. The efficient uptake in colonic epithelial cells exhibiting CD98 overexpression was demonstrated by in vitro and in vivo studies, determining a relief of IBD symptoms.  
Nanoparticles containing surface CD98 antibody in hydrogel formulation, with high affinity for CD98-overexpressing cells, were able to facilitate targeted drug delivery and down-regulate CD98. These nanobiosystems significantly reduced IBD symptoms in mice, both in vivo and in vitro, in the T cell transfer model of chronic colitis, and the DSS-induced model of colitis.  
Alginate and chitosan nanoparticles were engineered to deliver an anti-inflammatory tripeptide lysine-proline-valine (KPV) to the colon, optimizing the synthesis process by successfully encapsulating various water-soluble molecules, such as prohibitin and small interfering RNA [12].  
Oral gavage of KPV NPs to mice treated with DSS showed that the nanocarrier was able to overcome multiple physiological barriers and deliver the drug to the inflamed colon at concentrations 1200 times lower than free KPV solution, yielding similar therapeutic benefits.  
Enhanced cellular uptake of nanoparticles allows for reduced drug doses needed to induce a strong therapeutic effect. Using in vivo testing platforms, the authors showed that 60 ug kg\({}^{-1}\) TNF-\(\alpha\) siRNA were sufficient for silencing the TNF\(\alpha\) transcription by 60% when delivered to intestinal macrophages, with approximately a third of the macrophages being able to assimilate the nanoparticles carrying TNF-\(\alpha\) siRNA.