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

ABSTRACT 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.