Tumor/Lymph Node Dual-Targeting Ultrasonic Nanoconverter Orchestrates Spatiotemporal ROS Regulation for Dual-Zone Programmed Sono-STING Immunotherapy.

Tumor-draining lymph node (tdLN) metastasis remains a formidable challenge in treating breast cancer. Current anticancer treatments encounter difficulties in delivering therapeutic agents to tumors and tdLNs, impeding effective inhibition of tumor invasion and metastasis. Herein, a dual-targeting ultrasonic nanoconverter (OPD@PSF) is elaborately engineered through in situ polymerization to co-deliver a sonosensitizer protoporphyrin IX (PpIX) and a stimulator of interferon genes (STING) agonist Vadimezan (DMXAA) to achieve dual-zone programmed sono-STING immunotherapy (DPSSI) in tumors and tdLNs. Following peritumoral administration, OPD@PSF preferentially accumulates in both the tumors and tdLNs via the enhanced permeability and retention (EPR) effect and lymphatic drainage, respectively. Upon high-power ultrasound (US) irradiation at the tumor site, OPD@PSF induces substantial reactive oxygen species (ROS) generation for sonodynamic therapy (SDT), thereby triggering immunogenic cell death. Meanwhile, low-power US exposure in the tdLNs produces moderate ROS levels, promoting immune cell activation and hindering lymphatic metastasis. Additionally, DMXAA-mediated STING activation stimulates antigen-presenting cells, acting synergistically with ROS-driven SDT to eradicate primary tumors and suppress metastatic dissemination. By optimizing the US parameters, the rationally designed OPD@PSF exemplifies a new nanotechnological strategy for synergistic breast cancer therapy and metastasis suppression via tumor/tdLN dual-targeted delivery and systemic immune orchestration, holding great promise for clinical translation.