Photosensitive Ropivacaine- and Chlorin e6-Loaded Hydrogel Targeting the Substance P-Tachykinin Receptor 1-Toll-like Receptor 7 Axis Enhances Photodynamic and Photothermal Therapy Against Oral Cancer.

Abstract

This study examines the important role of neuro-tumoral crosstalk in oral squamous cell carcinoma (OSCC) progression and therapy. We identified that dorsal root ganglia (DRG)-secreted substance P (SP) activates a pro-metastatic Tacr1-Tlr7 neuroinflammatory axis. To therapeutically disrupt this axis, a multifunctional photosensitive hydrogel patch (PDA/Rop-Ce6@DA-HA) was engineered. This patch co-delivers the local anesthetic ropivacaine (Rop) to block SP release from neurons and the photosensitizer chlorin e6 (Ce6) for combined photothermal (PTT) and photodynamic therapy (PDT). Under near-infrared irradiation, the patch enabled controlled drug release and synergistic PTT/PDT effects. In orthotopic and subcutaneous OSCC models, this combinatorial strategy markedly reduced SP levels, inhibited the Tacr1-Tlr7 axis and downstream PI3K/Akt signaling, increased tumor cell apoptosis, and produced stronger antitumor effects. The results support a biomaterial-based strategy that combines local neuromodulation with phototherapy for OSCC treatment. STATEMENT OF SIGNIFICANCE: This study develops a photosensitive PDA/Rop-Ce6@DA-HA hydrogel patch that integrates photothermal therapy, photodynamic therapy, and local neural modulation for oral squamous cell carcinoma. By blocking DRG-derived substance P release and suppressing the SP-Tacr1-Tlr7 axis, the biomaterial targets neuro-tumoral crosstalk while enabling localized light-triggered tumor ablation. The work links biomaterial design with a defined neuroinflammatory mechanism and provides a combined strategy for improving oral cancer treatment.