Engineering sampling microneedles for biomolecules sensing

Interstitial fluid (ISF), located in superficial tissues, has garnered significant attention for its rich composition of biological substances. Sampling microneedles (MNs) are particularly well-suited for sensing these biomolecules due to their minimally invasive nature, reduced discomfort, in-situ diagnostic capabilities, and compatibility with various technologies. This review aims to summarize up-to-date advancements in the customization of MNs for emerging biosensing technologies targeting ISF biomolecules. First, the sensing applications of different types of MNs are comprehensively introduced, with a focus on tailoring biorecognition components or integrating biosensors to analyze nucleic acids, proteins and exosomes, lactate, glucose, various ions, and other small molecules. We then specialize in different sensing modes, including offline, optical, and electrochemical approaches, along with examination techniques such as quantitative fluorescence analysis, visual result interpretation, and flexible electronics customization. Furthermore, wearable and implantable MN devices for closedloop and continuous monitoring are highlighted, emphasizing their roles in accurate therapeutic drug management for localized extra-organ diseases, real-time treatment progress monitoring, and disease prognosis. Moreover, we briefly discuss MN-based electrophysiological measurements and other promising applicable sensing technologies currently in the proof-of-concept stage with buffer or surrogate solutions. Finally, the challenges and future perspectives of MNs for ISF biomolecular sensing are outlined.