Angiopep-2 functionalized poly(lactic-co-glycolic acid) nanocomposite for synergistic chemo-immunotherapy in glioma through STING pathway activation

Effective treatment of glioma remains challenging due to the limited permeability of the blood–brain barrier (BBB) and the highly immunosuppressive tumor microenvironment. To address these obstacles, we develop a multifunctional nanocomposite, Ang-PMT, that enables synergistic chemo-immunotherapy by enhancing BBB penetration and amplifying activation of the stimulator of interferon genes (STING) pathway. Ang-PMT consists of poly(lactic-co-glycolic acid) (PLGA) conjugated with angiopep-2 (Ang) and encapsulates manganese dioxide (MnO2) nanoparticles and triphenylphosphonium modified doxorubicin (TPP-DOX). Ang-PMT efficiently traverses the BBB via Ang-mediated transcytosis and selectively targets glioma cells through mitochondrial localization conferred by the TPP moiety. Upon exposure to intracellular glutathione, Ang-PMT rapidly degrades, releasing DOX and generating Mn2+ ions that synergistically activate STING signaling and induce immunogenic cell death, thereby amplifying therapeutic efficacy. Consequently, Ang-PMT enables precise drug delivery and achieves potent synergistic inhibition of tumor growth, significantly outperforming TPP-DOX, Ang-PM, and Ang-PT treatments.