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Current anticancer treatments encounter difficulties in delivering therapeutic agents to tumors and tdLNs, impeding effective inhibition of tumor invasion and metastasis. Herein, a dual\u2010targeting ultrasonic nanoconverter (OPD@PSF) is elaborately engineered through in situ polymerization to co\u2010deliver a sonosensitizer protoporphyrin IX (PpIX) and a stimulator of interferon genes (STING) agonist Vadimezan (DMXAA) to achieve dual\u2010zone programmed sono\u2010STING 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\u2010power 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\u2010power US exposure in the tdLNs produces moderate ROS levels, promoting immune cell activation and hindering lymphatic metastasis. Additionally, DMXAA\u2010mediated STING activation stimulates antigen\u2010presenting cells, acting synergistically with ROS\u2010driven 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\u2010targeted delivery and systemic immune orchestration, holding great promise for clinical translation.<\/jats:p>","DOI":"10.1002\/smll.202600058","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:41:33Z","timestamp":1777448493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\/Lymph Node Dual\u2010Targeting Ultrasonic Nanoconverter Orchestrates Spatiotemporal ROS Regulation for Dual\u2010Zone Programmed Sono\u2010STING Immunotherapy"],"prefix":"10.1002","volume":"22","author":[{"given":"Minghao","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines Center of Advanced Pharmaceuticals and Biomaterials China Pharmaceutical 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