Yoda1-Loaded Microfibrous Scaffolds Accelerate Osteogenesis through Piezo1-F-Actin Pathway-Mediated YAP Nuclear Localization and Functionalization.

Yoda1 has been recognized as an effective pharmacological intervention for the treatment of critical bone defects. However, the local delivery strategy of Yoda1 is uncommon, and the underlying mechanism through which Yoda1 enhances osteogenesis has been poorly investigated. Here, we propose utilizing electrohydrodynamic (EHD)-printed microfibrous scaffolds as a drug carrier for loading Yoda1 through a polydopamine (PDA) coating, and the synthetic mechanisms for enhancing bone regeneration are explored. Yoda1 was successfully loaded on the surface of the EHD-printed microfibrous scaffolds with the assistance of PDA. The results of experiments demonstrated that the Yoda1-loaded microfibrous scaffold group exhibited a more than 2-fold increase in COL-I protein levels compared to the control group. Additionally, the expression levels of osteogenic indicators such as ALP, Runx2, and OCN genes were significantly increased by 2-4-fold compared to those in the control group. We revealed that Yoda1 can effectively activate the Piezo1-F-actin pathway, thereby facilitating YAP nucleation and promoting lysine histone acetylation. Consequently, this mechanism enhanced the functionality of YAP nucleation and upregulated the expression of COL-I. Moreover, when implanted , the Yoda1-loaded microfibrous scaffold group could promote macrophage M2 polarization, thereby enhancing bone regeneration at defect sites. It is believed that the localized release of Yoda1 via EHD-printed PCL scaffolds might represent a promising strategy for the clinically precise treatment of bone defects.