Unlocking Wnt's weak spot: Glycosylated nanoalbumins to reignite immune responses 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.