Hydrogel-mediated tri-modal nanoplatform for localized colorectal cancer therapy via smart chemo–photothermal–radiotherapy

Colorectal cancer (CRC) remains difficult to eradicate locally because chemotherapy, photothermal therapy (PTT), and radiotherapy each have distinct limitations when used alone. Here, we engineer an injectable, mucoadhesive hydrogel-mediated tri-modal nanoplatform designed for localized CRC therapy by integrating smart chemotherapy delivery with externally activatable PTT and radiosensitization. Core-shell AuNP@mesoporous silica nanoparticles were loaded with 5-fluorouracil (5-FU) and functionalized with a pH/ROS-responsive linker and hyaluronic acid (HA) to enable CD44-mediated tumor targeting and microenvironment-triggered "uncapping"/drug release. The targeted nanocarriers were embedded within a chitosan/acellular fish skin (CS/AFS) hydrogel to form a local depot intended to prolong tumor-site residence and reduce systemic exposure. In vitro, the complete nine-group panel demonstrated stepwise gains from targeting, hydrogel confinement, and external activation. The tri-modal condition (Gel-tNP + 808-nm NIR + 2-Gy X-ray) produced the strongest cytotoxicity, approaching near-complete ablation in HCT-116 cells and reproducing the efficacy hierarchy in a second CRC line (SW480), while normal colon epithelial cells (NCM460) maintained higher viability across matched conditions, supporting an initial therapeutic window. Mechanistically, the tri-modal regimen generated the highest intracellular ROS levels, amplified early γH2AX DNA double-strand break signaling and increased damage persistence, and drove extensive cell death consistent with synergistic chemo-photothermal-radiotherapy action (e.g., ~ 9% viability and ~ 5.6-fold LDH release vs. control in the tri-modal group). Collectively, this work advances an engineering framework for localized, externally programmable tri-modal CRC therapy using a stimuli-responsive, HA-targeted nanocarrier embedded in an injectable bioadhesive hydrogel depot.