Enzyme/Reactive Oxygen Species-Dually Activated Hyaluronic Acid Nanocarriers Enable Celastrol Delivery for Site-Specific Therapy of Inflammatory Bowel Diseases and Colorectal Cancer

Introduction: Conventional oral nanocarriers for intestinal diseases rely on single-responsive mechanisms and target a single pathological stage, failing to address the inflammation–carcinoma continuum. Celastrol (Cel)’s oral translation is limited by poor bioavailability and lack of lesion-specific targeting. To overcome these barriers, we constructed a hyaluronic acid (HA)-functionalized platform featuring dual enzyme/ROS-triggered release and CD44-mediated active targeting (HA@Cel/NPs) for treating ulcerative colitis (UC), colitis-associated colorectal cancer (CAC), and colon cancer.Methods: HA@Cel/NPs were fabricated using β-cyclodextrin and 4-(hydroxymethyl) phenylboronic acid as dual-responsive linkers. Physicochemical properties, drug release profiles, cellular uptake, anti-inflammatory activity, macrophage polarization, and anticancer activity were systematically evaluated in vitro. In vivo biodistribution and therapeutic efficacy were assessed in UC, CAC, and colon cancer mouse models, with anti-PD-L1 combination therapy in the colon cancer setting.Results: HA@Cel/NPs exhibited uniform size (76.87 ± 2.65 nm, PDI 0.166 ± 0.012), stayed stable for 14 days, and achieved ~71% Cel release under high H2O2/α-amylase conditions within 8 h. The nanocarriers enhanced cellular uptake and promoted M1-to-M2 macrophage polarization in inflamed macrophages, while inducing potent CT26 cell apoptosis. Orally administered HA@Cel/NPs alleviated UC severity and suppressed CAC progression, with significantly reduced tumor burden. In colon cancer, intravenous HA@Cel/NPs combined with intraperitoneal anti-PD-L1 significantly boosted CD8⁺ and CD4⁺ T cell infiltration and effectively eradicated established tumors compared with HA@Cel/NPs monotherapy.Conclusion: HA@Cel/NPs offer a versatile, dual-route platform that bridges inflammation management and cancer immunotherapy, distinguishing itself from single-mechanism or single-disease nanocarriers.