A Manganese‐Based Nanodriver Coordinates Tumor Prevention and Suppression through STING Activation in Glioblastoma

Abstract

Glioblastoma (GBM), the most prevalent and aggressive primary malignant brain tumor, exhibits profound immunosuppression and demonstrates a low response rate to current immunotherapy strategies. Manganese cations (Mn2+) directly activate the cGAS/STING pathway and induce the unique catalytic synthesis of 2′3'‐cGAMP to facilitate type I IFN production, thereby enhancing innate immunity. Here, a telodendrimer and Mn2+‐based nano‐driver (PLHM) with a small size was developed, which effectively targeted lymph nodes through the blood circulation and exhibited tumor‐preventive effects at low doses of Mn2+ (3.7 mg kg–1). On the other hand, the PLHM nano‐driver also exhibited apparent anti‐tumor effects in GBM‐bearing mice via inducing in vivo innate immune responses. The combination of PLHM with doxorubicin nanoparticles (PLHM‐DOX NPs) resulted in superior inhibition of tumor growth in GBM‐bearing mice due to the synergistic potentiation of STING pathway functionality by Mn2+ and the presence of cytoplasmic DNA. Our findings demonstrate that PLHM‐DOX NPs effectively stimulated innate immunity, promoted dendritic cell maturation, and orchestrated cascaded infiltration of CD8 cytotoxic T lymphocytes within glioblastomas characterized by low immunogenicity. These nano‐divers chelated with Mn2+ show promising potential for tumor prevention and anti‐tumor effects on glioblastoma by activating the STING pathway.This article is protected by copyright. All rights reserved

Emerging Cationic Nanovaccines

“…The NPs' ability to target lymph nodes and facilitate DC maturation and antigen presentation is illustrated by the development of a manganese-based nanodriver. This delivery system efficiently activates the stimulator of interferon genes (STING) pathway directly within the cytoplasm, promoting the production of type I interferon and enhancing the immune response against glioblastoma; the incorporation of doxorubicin in the NPs further amplifies this effect, demonstrating a potent synergistic interaction between the drug and the antigen that enhances tumor suppression [54].…”

Applications of nanotechnology in remodeling the tumour microenvironment for glioblastoma treatment

“…111,112 Zhang et al utilized a copolymer formed by PEG 5000 , seven lysines, and eight histidines to chelate Mn 2+ and simultaneously carry DOX, creating a nanodriver (PLHM-DOX) for GBM treatment. 73 The combination of Mn 2+ and DOX not only regulates STING signaling but also induces cell apoptosis, synergistically activating the immune response. PLHM-DOX NPs significantly increase the expression of cGAS and STING in GL261 cells in vitro and effectively activate innate immunity, induce DCs maturation, and promote CD8 + T cell maturation in vivo .…”