In precision medicine, genomics, proteomics, forensic toxicology, and environmental trace monitoring, Mass Spectrometry (MS) and High-Performance Liquid Chromatography (HPLC) serve as gold-standard analytical instruments. However, in complex biological matrices (such as whole blood, saliva, urine, or single-cell lysates), target analytes (e.g., low-abundance protein disease biomarkers, trace pharmaceutical metabolites, or circulating cell-free nucleic acids) often exist at extremely low concentrations (attomolar $text{aM}$ to femtomolar $text{fM}$ ranges). These targets are surrounded by high concentrations of interfering proteins, lipids, and inorganic salts. Without sample extraction, cleanup, and preconcentration, target signals are obscured by baseline noise, preventing accurate quantification.

Standard solid-phase extraction (SPE) packed beds and microfluidic concentration channels present operational drawbacks, including high hydraulic flow resistance, limited extraction capacities, non-specific sample loss, and channel clogging. Aerogels—functioning as solid media featuring large pore volumes, high specific surface areas, and continuous nano-scale flow pathways—are being integrated into microfluidic chips (Lab-on-a-Chip) and mass spectrometry front-end interfaces, providing analytical sensitivity and sample preparation capabilities.

Employing in-situ sol-gel polymerization, analytical chemists synthesize silica, organic polymer, or carbon aerogels within microfluidic channels, forming monolithic aerogel micro-columns. The high specific surface area provides a high spatial density of active adsorption sites. Concurrently, the interconnected nanoporous network allows liquid samples to pass through the aerogel matrix with minimal hydraulic resistance under microfluidic pumping, shortening molecular diffusion distances.

By introducing functional chemistry onto the aerogel framework (such as C18 alkyl chains, hydrophilic interaction groups, ion-exchange moieties, or immobilized antibodies/aptamers), monolithic aerogel columns exhibit chemical selectivity. When microliter-volume biological samples transit the aerogel domain, trace target molecules (e.g., specific phosphopeptides or genomic DNA fragments) are captured and concentrated within the pore structures, while interfering salts and background proteins are washed away. Subsequently, a nanoliter-volume eluent plug desorbs the concentrated analytes for direct mass spectrometric analysis, achieving concentration factors up to several orders of magnitude.

Additionally, functional aerogels act as matrix-free targets for Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS). Utilizing the broadband photothermal absorption of carbon or metal-oxide aerogels, the porous matrix absorbs laser energy and transfers it to captured trace analytes, eliminating matrix background interference in the low-mass spectrum. The synergy between aerogel materials, microfluidics, and mass spectrometry is creating tools for single-cell analytics, early-stage cancer liquid biopsies, and point-of-care diagnostics (POCT).