Exploring adhesion forces in biological systems by atomic force microscopy: from nonspecific interactions to molecular recognition

Adhesion is a fundamental biophysical property describing how biological systems establish, maintain, and remodel interactions with their surrounding environment. Force spectroscopy, based on Atomic Force Microscopy (AFM), has emerged as a powerful approach for investigating these nanoscale interactions under physiologically relevant conditions. While existing literature often presents AFM as a general tool for nanomechanics or cellular topography, this review addresses a critical gap by focusing specifically and systematically on biological adhesion as a multidimensional mechanochemical phenomenon. We emphasize that biological adhesion cannot be reduced to a single scalar pull-off force; instead, AFM force-distance curves encode complex biophysical signatures that integrate force magnitude, adhesion energy, interaction range, rupture dynamics, and mechanically mediated detachment processes. In this review, we synthesize the physical foundations of adhesion, including nonspecific physicochemical forces, molecular recognition, polymer dynamics, and mechanical coupling, and demonstrate how these mechanisms translate directly into AFM force curves for cells, tissues, biomaterials, microorganisms, pathogen-modified host cells, and viral particles. We place special emphasis on the contrast between non-functionalized probes, which provide global adhesive fingerprints, and functionalized probes, which enable selected molecular interactions to be probed with piconewton-level sensitivity. Finally, we discuss current limitations and future perspectives regarding experimental standardization, statistical robustness, automated force-curve classification, and multimodal integration. By establishing a unified framework connecting fundamental physical forces, force-curve shape analysis, and biological applications, this review fills an essential gap for researchers seeking to decipher adhesion mechanisms at biological interfaces and within complex living systems.