Intratumoral Bacterial-Targeted Cascade-Responsive Sonoafterglow Nanoprobes for Immune Reprogramming and Visualization in Glioblastoma

Bacteria within glioblastoma (GBM) promote tumor progression and immunosuppression, while current treatments face challenges such as poor blood-brain barrier (BBB) penetration and immunosuppressive macrophages. To overcome these, we developed cascade-responsive sonoafterglow nanoprobes for bacteria-targeting, immune reprogramming, and imaging. These nanoprobes, incorporating a sonoafterglow pro-substrate, sonosensitizer, and maltodextrin, selectively targeted bacteria via the ATP-binding cassette sugar transporter pathway. Delivered through ultrasound (US)-induced BBB opening, they achieved a 1.5-fold enhancement in GBM accumulation. Upon US activation, they generated singlet oxygen (¹O₂), eradicating bacteria, ablating tumor cells, and reprogramming macrophages to a pro-inflammatory state secreting peroxynitrite (ONOO^-). This cascade-responsive system enabled precise afterglow activation via ¹O₂ and ONOO^- interactions, achieving real-time imaging of the tumor immune microenvironment. Integrating bacterial targeting, immune modulation, and imaging, this platform presents a promising GBM therapy.