Multitargeted Degradation of Cell Surface Receptors by Modular Glyco-Nanosheets

Targeted protein degradation mediated by antibodies represents a powerful approach for eliminating cell surface proteins. However, most existing systems require the customized conjugation of antibodies to functional groups that mediate cellular endocytosis, thereby lacking structural universality and expandability. Herein, we developed a modular glyco-nanosheet platform for GLUT1-facilitated lysosomal degradation of cell-surface immune checkpoints, integrating a glucosyl polymer module for tumor-specific endocytosis and a protein A (ProA) module for universal antibody loading. By programming the spatial distribution of functional modules, we constructed three nanostructures with tunable antibody density and distribution. These nanosheets enabled efficient GLUT1-facilitated internalization and lysosomal trafficking, resulting in an effective single-target degradation of PD-L1 and simultaneous dual-target degradation of PD-L1/CD47. Under IFN-γ cotreatment, the dual-target nanosheets reduced the relative viability of cancer cells to ∼30%, significantly outperforming single-target systems. This modular, target-expandable glyco-nanosheet provides a universal strategy for multitargeted TPD and shows great potential for precision immunotherapy.