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Quantitative and Reversible Regulation of Yes-Associated Protein Activity by Ultrasmall Nanoparticle-Mediated Magnetothermal Stimulation of F-Actin Yes-associated protein (YAP) is a mechanosensory protein that serves as a critical transcriptional coactivator involved in various cellular processes. Thus, the precise regulation of YAP is vital for effectively manipulating cellular functions. Despite small molecular inhibitors and siRNA being available, these approaches often fail to achieve precise and reversible regulation of YAP dynamics within complex biological systems. This often leads to suboptimal therapeutic results or collateral damage to healthy tissues. Here, we introduce a method for quantitative and reversible regulation of YAP through nanoparticle-mediated magnetothermal stimulation of F-actin, which is crucial for transmitting mechanical signals to YAP. We utilized actin-binding peptide-modified ultrasmall zinc-doped ferrite nanoparticles to specifically and effectively disrupt intracellular F-actin structures by generating localized heat upon exposure to an alternating magnetic field (AMF). In our in vitro studies, increasing the AMF intensity from 0 to 313 Oe led to a progressive deterioration of F-actin integrity, which was defined as Fint. Fint gradually decreased from 0.91 to 0.38 as the AMF intensity increased from 0 to 313 Oe. Concurrently, YAP nuclear localization also decreased, with the most rapid decline occurring within the range of 243–313 Oe. Importantly, cells were able to completely F-actin self-repair within 24 h, allowing YAP to re-enter the nucleus. This ability facilitates the quantitative and reversible control over YAP nuclear translocation. Further in vivo studies using MCF-7 tumor-bearing mouse models demonstrated the efficacy of this method in inhibiting glycolysis, reducing the ‘Warburg effect’, and reprogramming the tumor metabolic microenvironment. These results not only provide a promising strategy for precise manipulation of YAP nuclear localization but also establish a therapeutic framework for treating intractable diseases driven by YAP dysregulation. https://pubs.acs.org/doi/10.1021/acsnano.4c14672