In regenerative medicine, the temporospatially controlled delivery of growth factors (GFs) is crucial to trigger the desired healing mechanisms in the target tissues. The uncontrolled release of GFs has been demonstrated to cause severe side effects in the surrounding tissues. The aim of this study was to optimize a translational approach for the fine temporal and spatial control over the release of proteins, in vivo. Hence, we proposed a newly developed multiscale composite microspheres based on a core consisting of the nanostructured silicon multistage vector (MSV) and a poly(dl-lactide-co-glycolide) acid (PLGA) outer shell. Both the two components of the resulting composite microspheres (PLGA-MSV) can be independently tailored to achieve multiple release kinetics contributed to control the release profile of a reporter protein in vitro. It was investigated the influence of MSV shape (hemispherical or discoidal), size (1, 3 or 7 µm) on PLGA-MSV's morphology and size distribution. Secondly, we varied the copolymer ratio of the PLGA used to fabricate the outer shell of PLGA-MSV. The composites were fully characterized by optical microscopy, SEM, Zeta potential, FTIR and TGA-DSC, and their release kinetics over 30 days. PLGA-MSV biocompatibility was assessed in vitro with J77a macrophages. Remarkably, it was ultimately demonstrated that a zero-order release can be accomplished not only in vitro, but also in vivo, in a murine subcutaneous model. Herein, the release of a reporter protein was followed by intravital microscopy; PLGA-MSV was able to retain the payload over weeks, avoiding the initial burst release typical of most drug delivery systems. Finally, histological evaluation assessed the biocompatibility of the platform in vivo.