Divide and Conquer Strategy Using Piezoelectric Nanofiber Scaffolds for Stage-Specific Delivery of Bone-Targeted Exosome Mimetics with Ago/AntagomiR-126

Abstract

Bone regeneration is a temporally regulated process requiring stage-specific biochemical cues and biomechanical stimulation; however, current scaffold-based delivery systems largely rely on passive release and fail to adapt to the dynamic healing phases. While previous PVDF-based scaffolds have focused on enhancing piezoelectric output or osteoconductive properties, they primarily function as passive materials without the dynamic regulation of therapeutic activity. Here, we present a multifunctional piezoelectric scaffold that enables mechanically triggered, temporally controlled delivery of bone-targeted exosome mimetics (EMs) loaded with AgomiR or AntagomiR-126. The scaffold features a three-dimensional piezoelectric architecture that generates electromechanical activation under physiological loading, allowing for coupling between mechanical stimulation and therapeutic release. In addition, these components are functionally integrated to coordinate phase-specific miRNA activity during the repair. Alendronate-functionalized EMs enable bone-selective localization, while AgomiR-126 promotes early angiogenesis and progenitor recruitment and AntagomiR-126 enhances late-stage osteogenic differentiation. In vivo studies demonstrated that this system significantly improved bone repair. Rather than introducing a new component, this work establishes a mechanically gated, temporally programmed miRNA delivery strategy for phase-specific bone regeneration.