Noninvasive Activationof Local and Systemic Immunitywith a Sequential-Targeting Sonodynamic Nanovaccine to Treat Glioblastoma

Glioblastoma (GBM) presents significant therapeutic challenges due to the blood–brain barrier (BBB), suppressive tumor immune microenvironment (TIME), and systemic immunosuppression with limited T cell reserves. We developed a sequential-targeting sonodynamic nanovaccine (Stars NV) that avoids circulating macrophage uptake, efficiently crosses the BBB, and sequentially targets tumor-associated macrophages (TAMs). Under ultrasound stimulation, Stars NV noninvasively ablates GBM and induces adaptive anti-GBM immunity, functioning as a personalized in situ vaccine. Simultaneously, it releases R848 to reprogram the suppressive TIME. Additionally, Stars NV activates systemic immunity, promoting T cell generation in the thymus, maturation in lymph nodes, circulation in the bloodstream, and recruitment into the reprogrammed TIME. In an intracranial GBM mouse model, Stars NV extended median survival from 23 to over 60 days, elevated the M1/M2 TAM ratio by 31-fold and tumor-infiltrating lymphocytes by 5.2-fold, and lowered the Tregs by 5.5-fold. It also boosted systemic immunity, increasing peripheral CD4⁺ and CD8⁺ T cells by 2.4-fold and 5.4-fold, respectively. The Stars NV initiates a self-reinforcing cycle of local and systemic immunity, offering a promising strategy for GBM that holds substantial potential to enhance therapeutic outcomes.