An Oral Biomimetic Hydrogel for Colon-Localized and Tumor-Targeted Sonodynamic Therapy of Colorectal Cancer.

Oral drug delivery systems show great promise for colorectal cancer (CRC) therapy but are limited by poor gastrointestinal stability, insufficient colon localization, and low tumor targeting. Here, we report an oral biomimetic hydrogel platform, SAM/Au-TiO2@Gel, for colon-localized and tumor-targeted sonodynamic therapy of CRC. Au deposition enhances the sonodynamic reactive oxygen species (ROS) generation capability of TiO2, while Staphylococcus aureus membrane (SAM) coating improves tumor targeting and uptake. Inulin hydrogel enables stable oral delivery and prolonged colonic retention. SAM/Au-TiO2@Gel achieved ∼10-fold higher tumor accumulation after oral administration and superior antitumor efficacy under ultrasound with good biosafety. Moreover, the treatment induced immunogenic cell death, promoted dendritic cell maturation and CD8+ T-cell activation, and was associated with changes in intestinal microbiota composition suggestive of partial restoration. Together, this platform provides a promising noninvasive strategy for overcoming barriers in oral CRC therapy and enabling precise sonodynamic treatment.