Lewis Acidic Metal–Organic Framework Assisted Ambient Liquid Extraction Mass Spectrometry Imaging for Enhancing the Coverage of Poorly Ionizable Lipids in Brain Tissue

The spatial distribution of lipidomes in tissues is of great importance in studies of living processes, diseases, and therapies. Mass spectrometry imaging (MSI) has become a critical technique for spatial lipidomics. However, MSI of low-abundance or poorly ionizable lipids is still challenging because of the ion suppression from high-abundance lipids. Here, a metal-organic framework (MOF) Zr₆O₄(OH)₄(1,3,5-Tris(4-carboxyphenyl) benzene)₂(triflate)₆(Zr₆OTf-BTB) was prepared and used for selective on-tissue adsorption of phospholipids to reduce ion suppression from them to poorly ionizable lipids. The results show that Zr₆OTf-BTB with strong Lewis acidic sites and a large specific surface area (647.9 m²·g^-1) could selectively adsorb phospholipids under 1% FA-MeOH. Adsorption efficiencies of phospholipids are 88.4-144.9 times higher than those of other neutral lipids. Moreover, the adsorption capacity and the adsorption kinetic rate constant of the new material to phospholipids are higher than those of Zr₆-BTB (242.72 vs 73.96 mg·g^-1, 0.0442 vs 0.0220 g·mg^-1·min^-1). A Zr₆OTf-BTB sheet was prepared by a lamination technique for on-tissue phospholipid adsorption from brain tissue. Then, the tissue section on the Zr₆OTf-BTB sheet was directly imaged via ambient liquid extraction-MSI with 1% FA-MeOH as the sampling solvent. The results showed that phospholipids could be 100% removed directly on tissue, and the detection coverage of the Zr₆OTf-BTB-enhanced MSI method to ceramides (Cers) and hexosylceramides (HexCers) was increased by 5-26 times compared with direct tissue MSI (26 vs 1 and 17 vs 3). The new method provides an efficient and convenient way to eliminate the ion suppression from phospholipids in MSI, largely improving the detection coverage of low-abundance and poorly ionizable lipids.