Smart dendrimer nanogels boost mRNA-based cancer therapy via synergistic glycolysis inhibition and immune activation

作者：Xianghao Xiao, Yue Gao, Aojie Li, Yiyang Jia, Jingjing Li, Mengjiao Zhang, Rensong Ji, Mingwu Shen, Andrij Pich, Xiangyang Shi · 发表于：Bioactive Materials · 年份：2025 · DOI：10.1016/j.bioactmat.2025.10.008 · 被引用次数：4 · 研究领域：RNA Interference and Gene Delivery、Dendrimers and Hyperbranched Polymers、Advanced biosensing and bioanalysis techniques

Cancer mRNA vaccine has emerged as a promising immunotherapy approach. However, development of functional vehicles for safe and efficient mRNA delivery into immune cells (e.g., dendritic cells, DCs) remains to be challenging, and most of the mRNA-based vaccines just act on immune cells for improved anticancer immunity without additional input to tackle cancer cells, ultimately limiting the anticancer efficacy. Herein, we report the development of pH-responsive dual-action dendrimer nanogels (DNGs) to deliver gp100 mRNA as a potential nanovaccine. Mannose-conjugated generation 3 poly(amidoamine) dendrimers were crosslinked through dual functional polyethylene glycol with both ends of aldehyde groups to form pH-responsive DNGs. The DNGs with a size of 45.7 nm show excellent colloidal stability and cytocompatibility and allow dual-actions for DC-targeted mRNA delivery and cancer cell glycolysis inhibition. In a subcutaneous mouse melanoma model, the DNG/mRNA vaccine exerted glycolytic inhibition effect and triggered robust antitumor immune responses to suppress the tumor growth, especially in combination with anti-PD-L1 antibody-mediated immune checkpoint blockade. Meanwhile, the local vaccination of the vaccine enabled effective tumor occurrence prevention. Such a DNG-based mRNA vaccine with dual actions on both DCs and cancer cells may be applied for improved immunotherapy of other cancer types. • Mannose-modified G3 dendrimers form pH-responsive DNGs via a microemulsion metho...