Nano STING Agonist Inhibits Brain Metastases of Solid Tumors through Synergistic Chemotherapy, STING Activation, and Vascular Disruption

Brain metastases (BrM) represent a frequent and devastating complication of advanced solid tumors, characterized by poor prognosis and limited therapeutic options due to the restrictive blood-brain barrier and an immunosuppressive tumor microenvironment (TME). Although the stimulator of interferon genes (STING) pathway is a promising immunotherapeutic target, its clinical application has been hampered by systemic toxicity, inadequate tumor selectivity, and insufficient delivery to intracranial sites. To overcome these challenges, we developed a composite nanosystem, (PC-A)/M nanoparticles, for the targeted codelivery of the STING agonist diABZI and paclitaxel (PTX). This system employs a dual-responsive mechanism based on pH and glutathione (GSH), where the nanoparticle structure first dissociates in the acidic TME to facilitate cellular uptake and subsequently releases its therapeutic cargo in response to the elevated intracellular GSH levels of cancer cells. PTX induces immunogenic cell death and direct apoptosis, while the STING agonist disrupts neovasculature and activates innate immunity to reprogram the local immune environment. This synergistic combination promotes dendritic cell maturation, M1 macrophage polarization, and cytotoxic T-cell recruitment. Our strategy aims to concurrently target primary tumors and BrM, establishing a durable antitumor immune response, and establishes a promising therapeutic strategy for solid tumor BrM.