Recent developments in microsampling for oligonucleotides and biologics bioanalysis.

Abstract

The expanding landscape of therapeutic modalities, including monoclonal antibodies and oligonucleotide-based drugs, has created a need for sensitive and efficient bioanalytical strategies. Traditional blood sampling approaches pose significant limitations, including volume constraints, patient burden, and increased study complexity. Microsampling provides a transformative alternative, enabling low-volume (<100 µL), minimally invasive sample collection while supporting serial sampling and improved translational study design. This review highlights recent advances in microsampling techniques, including dried blood spots (DBS), volumetric absorptive microsampling (VAMS), and capillary microsampling (CMS), with focus on applications to protein therapeutics and oligonucleotides. Selected biomarker and protein/proteomics applications are also discussed where they provide practical insight into microsampling implementation for larger modalities. Key challenges, including hematocrit effects, recovery, matrix-dependent bias, stability, collection-site effects, and sensitivity limitations, are discussed alongside innovations in hybridization-based extraction, ligand-binding assays, and LC-MS workflows that enable reliable quantitation in microliter-scale samples. Despite these advances, broader implementation in regulated settings remains limited by regulatory considerations and the need to demonstrate concordance with conventional sampling. Ongoing efforts to harmonize best practices and improve analytical robustness are expected to accelerate adoption. Overall, microsampling offers opportunities to reduce burden, enhance efficiency, and expand access to high-quality PK data across emerging therapeutic modalities.