<i>Lycium Barbarum</i> Polysaccharide‐based Hydrogel as a Novel Oral Colon‐Targeted Drug Delivery System for Enhanced MSS‐CRC Treatment by Macrophage Lipid Reprogramming

ABSTRACT Chemotherapy remains a standard treatment for microsatellite stable colorectal cancer (MSS‐CRC), but its efficacy is limited by immunosuppressive tumor microenvironment (TME) and limited tumor drug accumulation. Here, we utilize Lycium Barbarum polysaccharide (LBP) as the functional material to encapsulate Oxaliplatin (Oxa), forming the oral colon‐targeted drug delivery system (OCTDDS), Oxa@LBP gel, for ameliorating the immunosuppressive TME and enhancing tumor‐specific drug accumulation against MSS‐CRC. The results demonstrate that both LBP gel and Oxa@LBP gel exhibit a characteristic 3D porous structure with excellent intestinal adhesion properties. In vitro and in vivo release experiments show sustained‐release profile in colorectal region by Oxa@LBP gel. The accumulation efficiency in tumor tissues is approximately sixfold higher by Oxa@LBP gel compared to intravenously administered Oxa. In vivo antitumor experiment confirms Oxa@LBP gel significantly regresses tumors in orthotopic colorectal cancer mice and ameliorates the immunosuppressive TME. Furthermore, lipidomic and Western blot show that LBP gel plays an important role in TME regulation via M2‐phenotype macrophage repolarization by lipid reprogramming through TLR4‐IRF3‐LXRα‐Abca1/Abcg1 axis. In conclusion, this study highlights a novel OCTDDS by employing the functional material LBP as both the hydrogel matrix and the agent for macrophage lipid reprogramming, providing a promising strategy for clinical MSS‐CRC treatment.