Available online 24 July 2025, 101412

Developing a novel therapeutic agent based on enhanced macropinocytosis towards albumin and carbohydrates of microsatellite-stable colorectal cancer (MSS-CRC) cells (termed GHSACA).

GHSACA specifically internalizes into MSS-CRC cells through micropinocytosis and inhibits the Wnt/β-catenin signaling cascade.

GHSACA reactivates anti-tumor immunity with an excellent safety profile in vivo in MSS-CRC.

Microsatellite-stable colorectal cancer (MSS-CRC) is characterized by poor immune infiltration and immune evasion, leading to rapid tumor progression and limited efficacy of current immunotherapies. The bioinformatics analysis revealed that the hyperactivation of the Wnt/β-catenin signaling pathway in MSS-CRC is instrumental in mediating immune suppression. Although inhibiting this pathway presents a therapeutic opportunity, no Wnt inhibitors have been clinically approved due to Wnt's essential role in maintaining tissue homeostasis, with inhibition in normal cells causing significant toxicity. To address it, we discovered that Wnt activation in colorectal cancer cells enhances macropinocytosis, particularly favoring the uptake of glycosylated proteins to meet increased nutrient demands. Building on this insight, we developed a glycosylated human serum albumin (GHSA) co-assembled with carnosic acid (CA), termed glycosylated human serum albumin-carnosic acid (GHSACA), which is selectively internalized by Wnt-activated colorectal cancer cells. This approach not only reduces off-target toxicity but also effectively inhibits the Wnt pathway, resulting in notable tumor inhibition and immune reactivation in murine models, while maintaining a favorable safety profile. This strategy offers a promising therapeutic solution by combining selective Wnt inhibition with enhanced immune activation in MSS-CRC, and highlights the potential of leveraging disease-specific cellular uptake mechanisms for designing nanomedicines, advancing the development of precision-targeted cancer therapies.

Microsatellite-stable colorectal cancer

Wnt/β-catenin suppressor

glycosylated albumin

macropinocytosis

anti-tumor immunity

© 2025 The Author(s). Published by Elsevier B.V. on behalf of Xi’an Jiaotong University.