ABSTRACT Radiation-induced proctitis (RIP) is often considered a chronic inflammatory disease involving the rectum. Pathologic studies have shown patient symptoms are correlated with inflammatory lesions along the epithelium lining the rectum. This grant application proposes to combine novel sulfated anionic polysaccharides, semisynthetic glycosaminoglycan ethers (SAGEs) with silk- elastinlike protein polymer (SELP) matrices to deliver therapeutically relevant doses in the rectum via a precisely engineered in situ gelling enema. SELPs exist as aqueous solutions at room temperature, and form a solid hydrogel matrix at body temperature, enabling them to prevent rapid clearance of the SAGE and enhance its localization in the lumen of the rectum and lower bowel. We hypothesize that localized delivery of SAGE can protect the rectum from damage caused by radiotherapy and improve efficacy by ameliorating RIP. To test this hypothesis three specific aims are proposed: 1) To synthesize and characterize SELPs with appropriate rheological properties and release profiles for rectal delivery of SAGE; 2) To investigate the biodistribution and efficacy of SAGE delivered from SELP hydrogels in a murine model of radiation-induced proctitis; 3) To elucidate mast cells as a key effector cell type in radiation-induced proctitis and assess SAGE in SELP hydrogels’ ability to attenuate mast cell mediated proctitis. This proposal is translational in nature and innovative in the new indication for use of recombinant SELPs to deliver our patented SAGE compounds with potent anti-inflammatory and anti-pain properties. The project is significant in that it will reduce the adverse effects of RIP in the affected patient populations. This work will establish the early-stage preclinical validation for these two systems and provide detailed knowledge about the inflammation and pain attenuation properties of the SAGE-SELP compounds.