Direct construction of intrinsic dual-hydrophilic core-shell MOF@MOF for robust and highly specific N-glycopeptide...

The practical application of metal-organic frameworks (MOFs) for glycopeptide enrichment is often constrained by limitations in both enrichment performance and structural stability. Addressing this, we report a novel application of a dual-amino-functionalized core-shell MOF@MOF architecture NH₂-MIL-101(Cr)@UiO-66(Zr)-NH₂ (NH₂-MU) for N-glycopeptide enrichment without post-synthesis modification. This design integrates a high-surface-area NH₂-MIL-101(Cr) core with a chemically robust NH₂-UiO-66(Zr) shell. The intrinsic dual-hydrophilicity, arising from the amino groups on both MOF layers, provides abundant hydrophilic sites for highly specific N-glycopeptide capture via hydrophilic interaction chromatography (HILIC). Notably, NH₂-MU outperforms its shell counterpart in enrichment performance while surpassing its core counterpart in cycling stability. This heterostructure exhibits substantially enhanced reusability over three consecutive cycles, confirming that the core-shell architecture synergistically combines the enrichment performance of the core with the cycling stability of the shell. Its practical utility was validated by identifying 746 N-glycopeptides, 212 N-glycosylation sites, and 191 glycoproteins from only 100 µg of mouse liver protein digest. This work presents a strategic materials design that overcomes the stability-performance dilemma via a straightforward, modification-free route, offering a robust and recyclable platform for in-depth glycoproteome analysis in complex biological samples.