Work

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

Year: 2025

Type: article

Abstract: 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 method. • The pH-responsive DNGs deliver mRNA to DCs and act as a new cancer nanovaccine. • Mannose ligands enable DNGs with DC targeting and tumor glycolysis inhibition. • Vaccination of DNG/mgp100 prevents tumor occurrence. • The combination of DNG/mgp100 with anti-PD-L1 enhances antitumor immune response.

Source: Bioactive Materials

DOI: 10.1016/j.bioactmat.2025.10.008