Injectable Dual-Drug Hydrogel For Oral Squamous Cell Carcinoma Therapy

This study aimed to develop a localized immunotherapy for oral squamous cell carcinoma (OSCC) using a pH/ROS responsive hydrogel co-loaded with B7-H3 blockade antibody and Cl-amidine. A tumor microenvironment-responsive hydrogel (Hydrogel@Anti-B7-H3&Cl-amidine) was constructed to enable dual-drug release. Subcutaneous and orthotopic OSCC mouse models were established to evaluate therapeutic efficacy, safety, and mechanisms. All animal experiments in this study were approved by the Institutional Animal Ethics Committee. The B7-H3 and neutrophil extracellular trap (NET) regulated epithelial mesenchymal transition (EMT) pathways were analyzed using qRT-PCR, Western blot, immunofluorescence, and flow cytometry, with experimental confirmation that downregulating B7-H3 and NETs effectively blocked the EMT process. The hydrogel demonstrated pH/ROS-triggered drug release, significantly inhibiting tumor growth and metastasis in both models. B7-H3 and NETs promoted OSCC metastasis by activating EMT, while the dual-drug hydrogel blocked EMT via B7-H3 antibody mediated immune activation and Cl-amidine induced NETs suppression. Local treatment enhanced CD4+/CD8+ T cell infiltration, reduced Ki67 expression, and elevated TUNEL positivity. The pH/ROS responsive Hydrogel@Anti-B7-H3&Cl-amidine delivery effectively suppresses OSCC progression by targeting immune checkpoints and NETs driven EMT, offering a safe and precise strategy for OSCC therapy.