Oral Delivery of Dendrimer-Derived siRNA-Nanogels Targeting Prostaglandin Metabolism Mitigates Gut Inflammation

Inflammatory bowel disease (IBD) is characterized by chronic immune-mediated inflammation of the gastrointestinal tract, with overexpression of cyclooxygenase-2 (COX2) playing a significant role in enhancing the pro-inflammatory cascade. Here, we present the engineering of an orally administered siRNA-nanogel formulation that alleviates intestinal inflammation by inhibiting COX2 expression. We prepared the nanogel (NG) by complexing COX2-targeting siRNA with a specially designed polymer having dendritic cationic pendants (DB) and then subsequently coating the complex with various negatively charged polymers such as hyaluronic acid (HA), sodium alginate (SA), carboxymethyl cellulose (CMC), and pectin (PA) to enhance cell viability and stability. Among the different siRNA nanogels explored, those formulated with HA (siCOX2-NGs) demonstrated the most effective therapeutic outcome upon oral delivery in a murine DSS (dextran sodium sulfate)-induced colitis model. These nanogels significantly reduced intestinal inflammation, enhanced clinical parameters, and restored the colon length and weight. Inhibition of COX2 led to successful downregulation of prostaglandin signaling by reducing prostaglandin levels in inflamed colon tissue. These findings highlight the therapeutic potential of oral delivery of COX2 siRNA using HA-coated nanogels (siCOX2-NGs) as a viable approach for managing IBD.