Charged dendrimers reduce glioblastoma viability by modulating lysosomal activity and HMGB1-RAGE interaction.

Dendrimers and dendrimer-based self-assembly systems have emerged as promising nanocarriers for a variety of applications, including anti-cancer therapies, modulation of the tumor microenvironment, and imaging. Here, we explored the therapeutic potential of two charged dendrimers, dendritic polyglycerol sulfate (dPGS) and dendritic polyglycerol amine (dPGA), in the context of glioblastoma multiforme (GBM). Docosahexaenoic acid (DHA) has shown potential in GBM. We therefore examined dPGS and dPGA effects alone and in combination with DHA. Using 2D cell models and 3D tumoroids, we showed that DHA with dPGA reduced tumor integrity and cell viability. dPGS reduced oxidative stress, whereas dPGA reduced lysosomal acidification, contributing to cellular dysfunction. Both dendrimers influence the interaction between high mobility group box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). The surfaces of the HMGB1-RAGE complex provide binding sites for interactions of charged molecules like dPGS and dPGA, suggesting the contribution of these interactions to cytotoxicity. In summary, our findings show that combining DHA with charged dendrimers (dPGS and dPGA) enhances GBM cytotoxicity through several mechanisms, involving lysosomal alkalinization, lipid peroxidation and modulation of the HMGB1-RAGE complex.