Quinone-amine sonosensitizer nanoplatform loaded with a GSDMD-activating agent for dual-pathway pyroptosis-augmented...

Glioblastoma (GBM) treatment is limited by the blood-brain barrier (BBB), insufficient sonodynamic efficacy, and an immunosuppressive tumor microenvironment. Here, we developed PG@dOMV, a dOMV-coated nanoplatform co-delivering a quinone-amine polymer sonosensitizer (PQANS) and a GSDMD-activating agent (GA) to integrate sonodynamic therapy with GSDMD-dependent pyroptosis. PQANS exhibited a donor-acceptor structure with a calculated HOMO-LUMO gap of 2.04 eV and a singlet-triplet energy gap of 0.78 eV, supporting ultrasound-responsive generation of singlet oxygen and other DHR123-reactive oxidative species. Under ultrasound irradiation, PG@dOMV activated the ROS/caspase-1/GSDMD-N pathway, whereas GA contributed to GSDMD-dependent membrane permeabilization without detectable GSDMD cleavage. GSDMD knockdown and disulfiram treatment attenuated IL-1β, IL-18, and LDH release, supporting the involvement of GSDMD pore-forming activity. The dOMV coating prolonged systemic retention and increased brain-associated accumulation. In an orthotopic GL261 model, PG@dOMV combined with ultrasound suppressed tumor progression and prolonged survival. CyTOF profiling further revealed treatment-associated remodeling of lymphoid and myeloid populations, including reduced Treg representation and enrichment of CD4⁺, CD8⁺, and effector-memory-like T-cell phenotypes. These findings support a biomaterial-based strategy integrating ultrasound-responsive oxidative damage, GSDMD-dependent pyroptosis, and immune-microenvironment remodeling for glioblastoma treatment. STATEMENT OF SIGNIFICANCE: Glioblastoma remains difficult to treat because many therapeutics do not efficiently reach the brain, sonodynamic therapy alone produces limited tumor damage, and the tumor microenvironment suppresses antitumor immunity. This study develops a dOMV-coated quinone-amine nanoplatform that combines ultrasound-triggered reactive oxygen species generation with GSDMD-dependent pyroptosis through two complementary pathways. The system enhances brain-associated delivery, suppresses orthotopic glioma growth, prolongs survival, and remodels immune-cell populations toward a more antitumor-associated state. Compared with existing sonodynamic platforms, this work links biomimetic delivery, polymer sonosensitization, pyroptotic cell death, and immune modulation in one material system. These findings may interest readers working in biomaterials, nanomedicine, tumor immunology, and brain-cancer therapy.