Rapid detection of monoamine neurotransmitters by carboxyl ionic organic crystal-functionalized paper spray mass spectrometry

The development of a mass spectrometry-based workflows for monoamine neurotransmitters (NTs) detection in biological samples is crucial for the accurate diagnosis of adrenal tumor. In this study, a carboxyl ionic organic crystal (CIOC) was synthesized via ion self-assembly of cationic and anionic monomers, featuring abundant carboxyl active sites for selective monoamine NTs capture. The CIOC-functionalized paper strips significantly enhance the sensitivity of direct capillary spray miniature mass spectrometry (DCS-mini MS) for monoamine NTs analysis. For biofluid analysis, the CIOC-functionalized paper strips were immersed in samples, washed with ACN to remove interferents, and analyzed by DCS-mini MS. Compared to unmodified paper strips, the CIOC-functionalized paper strips exhibited significantly enhanced sensitivity, with signal amplification factors of 7.6-fold for dopamine, 3.4-fold for norepinephrine, 4.6-fold for 5-hydroxytryptamine, and 5.6-fold for epinephrine in plasma, and corresponding increases of 10.9-fold, 4.0-fold, 6.3-fold, and 7.5-fold in urine. This is attributed to the synergistic effects of electrostatic interactions and hydrogen bonding between CIOC materials and the monoamine NTs. The method showed excellent linearity (R² > 0.9981), with LOD ranging from 0.51 to 2.11 ng mL⁻¹ in urine and 1.53–4.51 ng mL⁻¹ in plasma, and LOQ ranging from 1.7 to 7.01 ng mL⁻¹ in urine and 5.1–15.03 ng mL⁻¹ in plasma. The robustness of the method was confirmed through validation of precision (<10 % RSD) and recoveries (80.1–97.3 %). The CIOC@DCS-mini MS platform enables rapid (3 min), label-free clinical monoamine NTs monitoring, offering a precise solution for diagnosing monoamine NTs-related disorders.