Toward Comprehensive Sediment Nontarget Screening: A Multilayer Solid-Phase Extraction Workflow for Broader Chemical Space Coverage.

Conventional sample preparation in nontarget screening (NTS) often introduces physicochemical selectivity, limiting the detectable chemical space of complex environmental matrices prior to high-resolution mass spectrometry (HRMS). Systematic evaluation of single-layer solid-phase extraction (SPE) cartridges (HLB, PWAX/PWCX, C18, PS) revealed distinct, property-dependent applicability windows. To reduce extraction-induced selectivity, we developed a multilayer SPE (MLSPE) workflow enabling the broad-spectrum extraction of emerging contaminants (ECs) in sediments. By integrating complementary retention mechanisms, the optimized MLSPE achieved balanced extraction across an expansive physicochemical range (log Kow: -2.67 to 17.17; pKa: -1.81 to 12.27), significantly increasing the proportion of structurally diverse validation standards (>65%) falling within the 60%-120% recovery range. Coupled with complementary ionization (ESI/APCI) and hybrid acquisition (DDA/DIA), the workflow exhibited high sensitivity with method detection limits <1 ng/g (dry weight, d.w.) for 80% of compounds, and robust precision (RSDs < 20% for 83% of analytes). Quantitative accuracy was confirmed by the close agreement of the PFOS concentration (0.91 ± 0.02 ng/g d.w., n = 3) with the noncertified value (0.778 ± 0.046 ng/g d.w.) of the standard reference material (NIST SRM 1936). Application to SRM 1936 and field sediments yielded over 500 confident annotations. Notably, screening revealed elevated concentrations of quaternary ammonium compounds (QACs) and plasticizers that are frequently overlooked by routine monitoring yet heavily accumulated in urban-impacted sediment sinks. This coverage-oriented workflow reduces preanalytical selection for mapping the authentic sedimentary exposome, providing a comprehensive data foundation for holistic mixture-based ecological risk assessments.