Nanogels Targeting Post-translation Modifications help in Combating Gut Inflammation

Inflammatory bowel disease (IBD) is characterised by chronic inflammation of the gastrointestinal (GI) tract  and includes Chron’s disease and ulcerative colitis. Currently the treatment to this disease mainly involves immune-suppressants that often results in severe side effects.  To overcome poor success rates and challenges associated with current therapeutic strategies, Drs. Bajaj and Srikanth’s group tested  gene therapy as an alternative treatment option. However, oral delivery of nucleic acids (NAs) to an inflamed colon is challenged by multiple barriers presented by the GI tract. In the present work a range of different cationic polymersbased nanoparticles(in collaboration with Dr.Aasheesh Srivastava, IISER Bhopal), with varying hydrophobicity, were screened to finally pick TAC6 polymer which showed promising efficacy. TAC6 polymer were  able to deliver the NAs across mammalian cells using caveolae-mediated cellular uptake. TAC6 Nanogels loaded with NAs encoding  PIAS1 (protein inhibitor of activated STAT1), were engineered and directly tested in mice model of IBD. PIAS1 is a key nodal therapeutic target for IBD due to its ability to control NF-κB-mediated inflammatory signalling via SUMOylation pathway. We show that plasmid delivery using TAC6-derived nanogels diminished gut inflammation in a murine colitis model. Therefore, our study presents engineering of orally deliverable nanogels that can target SUMOylation machinery to combat gut inflammation with very high efficacy.

1. Reference: Yavvari, P. S.; Verma, P.; Mustfa, S. A.; Pal, S.; Kumar, S.; Awasthi, A. K.; Ahuja, V.; Srikanth, C. V.; Srivastava, A.; Bajaj, A. A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation. Nanoscale2019, 11, 4970–4986.