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© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim It is becoming more apparent in tissue engineering applications that fine temporal control of multiple therapeutics is desirable to modulate progenitor cell fate and function. Herein, the independent temporal control of the co-delivery of miR-148b and miR-21 mimic plasmonic nanoparticle conjugates to induce osteogenic differentiation of human adipose stem cells (hASCs), in a de novo fashion, is described. By applying a thermally labile retro-Diels–Alder caging and linkage chemistry, these miRNAs can be triggered to de-cage serially with discrete control of activation times. The method relies on illumination of the nanoparticles at their resonant wavelengths to generate sufficient local heating and trigger the untethering of the Diels–Alder cycloadduct. Characterization of the photothermal release using fluorophore-tagged miRNA mimics in vitro is carried out with fluorescence measurements, second harmonic generation, and confocal imaging. Osteogenesis of hASCs from the sequential co-delivery of miR-21 and miR-148b mimics is assessed using xylenol orange and alizarin red staining of deposited minerals, and quantitative polymerase chain reaction for gene expression of osteogenic markers. The results demonstrate that sequential miRNA mimic activation results in upregulation of osteogenic markers and mineralization relative to miR-148b alone, and co-activation of miR-148b and miR-21 at the same time.

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