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Abstract
Osteosarcoma treatment faces the dual challenges of poor drug delivery and limited immune therapy response. This study developed a bone-targeting, glutathione-responsive polymer nanoparticle that can chelate manganese ions and deliver ATM inhibitors and PRMT5 inhibitors. Through alendronate functionalization, this nanoparticle platform achieves preferential accumulation in bone tumors. After entering cells, high concentrations of glutathione trigger the controlled release of the two inhibitors. Inhibiting ATM and PRMT5 can amplify DNA damage and activate the cGAS-STING pathway, while manganese ions further enhance the innate immune signal by promoting cytoplasmic DNA sensing. These effects synergistically reshape the tumor microenvironment and promote anti-tumor immune responses. In vivo studies confirmed that this platform can significantly inhibit the progression of osteosarcoma and enhance the systemic immune response.
Research Highlights
This study constructed a bone-targeting, glutathione-responsive nanoparticle platform that integrates ATM/PRMT5 dual inhibitors and manganese ion immunostimulant into a single delivery system, achieving a synergistic effect of DNA damage amplification and innate immune activation. The bone-targeting strategy mediated by alendronate solved the problem of drug delivery in bone tissue, while the enhancement effect of manganese ions on the cGAS-STING pathway further amplified the immunotherapy effect, providing a new paradigm of "chemotherapy-immunotherapy" synergy for osteosarcoma.
Innovations
① Bone-targeted delivery: Alendronate functionalization enables the nanoparticle to accumulate preferentially in bone tumors;
② Dual inhibitor synergy: ATM and PRMT5 inhibitors are combined to amplify the DNA damage effect;
③ Manganese enhances immunity: Manganese ions promote cytoplasmic DNA sensing and further enhance the activation of the cGAS-STING pathway.
Material Development
1 Materials
Developed alendronate-functionalized bone-targeting, glutathione-responsive polymer nanoparticles that can chelate manganese ions and co-deliver ATM inhibitors and PRMT5 inhibitors.
2 Functions
This nanoparticle platform accumulates preferentially in bone tumors, responds to high concentrations of glutathione to release the dual inhibitors to amplify DNA damage and activate the cGAS-STING pathway, while manganese ions enhance the innate immune signal, synergistically reshaping the tumor microenvironment to promote anti-tumor immunity.
Thought Extension
This work provides a new idea for the targeted delivery and immune enhancement synergy strategy in osteosarcoma treatment. In the future, different bone-targeting ligands, release mechanisms, and DNA damage-innate immune coupling pathways can be explored for their universal application in other bone-related tumor models, further promoting the transformation of solid tumor immunotherapy from "single immune checkpoint blockade" to "reprogramming of tumor intrinsic immunogenicity".
Original Source
Bioactive Materials (IF 20.3) Pub Date : 2026-04-03,
DOI: 10.1016/j.bioactmat.2026.03.032 Zhaochen Tong, Yuezhan Li, Lingpu Zhang, Sijie Wen, Dong Wang, Zixin Li, Yi Peng, Weiguo Wang, Jinglei Miao, Haihua Xiao, Dabao Xu, Jinsong Li, Shijie Chen
