Glycated ECM Derived Carbon Dots Inhibit Tumor Vasculogenic Mimicry by Disrupting RAGE Nuclear Translocation and Its Interaction With HMGB1

Abstract This study investigates the role of advanced glycation end‐products (AGEs) in tumor vasculogenic mimicry (VM). Using high‐sugar diet animal models and glycated extracellular matrix (ECM) ex vivo models, AGEs derived is demonstrated from glycated ECM significantly enhanced tumor growth and VM formation. However, carbon dots (egCDs) derived from glycated ECM effectively inhibit tumor growth and VM formation in this glycated microenvironment. Mechanistic studies show that AGEs from glycated ECM bind to the Receptor of Advanced Glycation Endproducts (RAGE) receptors on tumor cells, promoting RAGE nuclear translocation and binding with high mobility group box 1 (HMGB1), which increases the transcription of Snail family transcriptional repressor 2 (SNAI2), thereby driving VM formation. However, egCDs competitively bind to RAGE, promoting its lysosomal degradation and blocking VM formation induced by the RAGE‐HMGB1‐SNAI2 axis. In conclusion, this study demonstrates that egCDs can target RAGE and promote its lysosomal degradation to block VM formation induced by glycated ECM. This finding not only reveals the transformation of glycated ECM from a pro‐VM factor to an anti‐VM therapeutic agent after carbonization, but also provides a theoretical basis for the innovative strategy of “reconstructing pathogenic substances into carbon dots to reverse disease‐driving factors into therapeutic targeting carriers”.