Sonodynamic Gnps United With Macrophages Reprogramming In Oral Cancer Therapy

This study aimed to investigate ultrasound (US)-induced pro-inflammatory polarization of macrophages via HMGB1-RAGE signaling and develop a therapeutic strategy combining US with tumor-targeting gold nanoparticles (GNP@EXO-APs) to reprogram tumor-associated macrophages (TAMs) and enhance oral cancer treatment. Mouse macrophages (RAW 264.7, mBMDM) were treated with US; morphological/phagocytic changes were assessed via atomic force microscopy, fluorescence, and transcriptomics. HMGB1 translocation and receptor interactions were analyzed using immunofluorescence, molecular docking (STRING/HDOCK), and WB. Bioinformatics (GSE datasets) evaluated TAMs in oral cancer. GNP@EXO-APs (exosome/aptamer-modified) were synthesized and tested for tumor targeting, cytotoxicity, and lysosome disruption under US. In vivo tumor targeting and therapeutic efficacy were validated via imaging, histology, and flow cytometry. US induced macrophage M1 polarization, reduced cell stiffness, enhanced phagocytosis, and triggered HMGB1 nuclear-to-cytoplasmic translocation, binding RAGE to activate pro-inflammatory pathways. GNP@EXO-APs targeted tumor cells via AS1411 aptamer, accumulated in lysosomes, and under US, induced lysosome-dependent cell death. In vivo, US+GNP@EXO-APs suppressed tumor growth, reprogrammed M2-like TAMs to M1-like phenotypes, and showed minimal systemic toxicity. US promotes macrophage pro-inflammatory polarization via HMGB1-RAGE signaling. Combined with tumor-targeted GNP@EXO-APs, US achieves dual mechanical tumor destruction and TAM reprogramming, offering a promising strategy for enhanced cancer immunotherapy and clinical translation.