Ultrasmall zwitterion-micelles coupled with anti-checkpoint antibody for overcoming glioma barriers to eliminate stem cells and amplify immunotherapy.

The efficacy of immune checkpoint blockade (ICB) against glioblastoma (GBM) is significantly constrained by the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment associated with glioma stem cells (GSCs). To address these challenges, anti-programmed death-ligand 1 antibodies (anti-PD-L1) are conjugated to ultra-small zwitterionic micelles (MCB) through pH-sensitive traceless linkers, followed by encapsulation of salinomycin (SAL) to construct multimodal zwitterionic micelles (MCB-PD@S). The resulting micelles efficiently cross the BBB via BGT-1-mediated active transport, exploit vesicular trafficking pathways in GBM vasculature for tumor-specific accumulation, and utilize their zwitterionic surface to enhance penetration into GSC niches through monocarboxylate transporters (MCTs). SAL-induced eradication of GSCs robustly stimulates immunogenic cell death, dendritic cell maturation, and subsequent T-cell activation. This effect is synergistically amplified by the release of structurally intact anti-PD-L1 within the acidic tumor microenvironment, collectively fostering potent and sustained antitumor immunity that effectively suppresses GBM recurrence. This work establishes a new paradigm in brain tumor therapy by simultaneously overcoming biological delivery barriers and immune evasion, offering a clinically translatable solution for post-resection GBM management.