Highly　efficient　extraction　of　phospho-and　glycopeptides　from　complicated　biological　samples　is　extremely　crucial　for　comprehensive　characterization　of　protein　phosphorylation　and　glycosylation　based　on　mass　spectrometry　(MS).　In　this　work,　a　new　synergistic　strategy　that　combined　surface　covalent　modification　and　alkaline　etching　was　developed　to　synthesize　hydrophilic　hollow　zirconium-organic　frameworks　(HHZr-MOFs)　for　simultaneous　recognition　and　capture　of　phospho-and　N-glycopeptides.　The　unique　properties　including　high　specific　surface　area,　mesoporous　shell　and　hollow　cavity　endowed　HHZr-MOFs　with　facilitated　mass　transport　and　abundant　accessible　active　sites.　Benefited　from　the　maltose　modified　on　the　external　surface　and　ZreO　clusters　retained　on　the　internal　surface,　HHZr-MOFs　could　act　as　a　highly　efficient　bifunctional　probe　for　simultaneous　enrichment　of　phospho-and　N-glycopeptides　based　on　hydrophilic　interaction　chromatography　(HILIC)　and　metal　oxide　affinity　chromatography　(MOAC),　respectively.　Finally,　a　total　of　98　endogenous　phosphopeptides　and　216　endogenous　N-glycopeptides　were　simultaneously　captured　by　HHZr-MOFs　from　saliva　samples　of　patients　with　oral　inflammation,　and　several　phospho-and　glycoproteins　related　with　coagulation,　bacterial　defense　and　immune　response　for　oral　inflammation　were　identified　by　Gene　ontology　(GO)　analyses,　confirming　the　great　potential　of　HHZr-MOFs　in　rapid　detection　of　clinical　biomarkers　and　comprehensive　profiling　of　phosphoproteomic　and　glycoproteomic　for　complex　biological　samples.　This　work　not　only　provides　an　alternative　method　to　precisely　design　and　synthesize　sophisticated　hollow　MOFs　with　multifunctionalities,　but　also　offers　a　novel　concept　of　multifunctional　material　design　for　bioseparation　and　analysis　in　modification-specific　proteomics.　(c)　2022　Elsevier　B.V.　All　rights　reserved.