Therapies based on oligonucleotides (OGN) often require multiple bioanalytical assay formats to measure the active pharmaceutical ingredient in tissues and fluids. Hybridization ELISA is used to measure the levels in fluids such as cerebral spinal fluid or plasma because the concentrations can be too low to detect with liquid chromatography mass spectrometry (LCMS). The levels in tissues are commonly measured by LC-MS/MS or LC-high resolution MS (LC-HRMS) as they are greater than liquid matrices. Regulatory agencies and innovators increasingly want to monitor additional components in OGN assays including glycoforms, shortmers, payloads, and other non-OGN constructs. The challenges are that hybridization ELISA lacks the specificity to monitor multiple components and LC-MS lacks the sensitivity to measure components in clinically relevant liquid matrices. We employed antisense capture to clean up and concentrate the samples to gain the sensitivity on the mass spectrometer to have quantitation limits comparable to hybridization ELISA. In this talk, the design of the capture probes will be discussed as well as the capture efficiency across various shortmer lengths and OGNs containing covalently attached small molecules.