The aim of this study was to evidence the ability of vegetable oil-based hybrid microparticles (HMP) to be an efficient and safe drug delivery system after subcutaneous administration. The HMP resulted from combination of a thermostabilized emulsification process and a sol-gel chemistry. First of all, castor oil was successfully silylated by means of (3-Isocyanatopropyl)trimethoxysilane in solvent-free and catalyst-free conditions. Estradiol, as a model drug, was dissolved in silylated castor oil (ICOm) prior to emulsification, and then an optimal sol-gel crosslinking was achieved inside the ICOm microdroplets. The resulting estradiol-loaded microparticles were around 80 µm in size and allowed to entrap 4 wt% estradiol. Their release kinetics in a PBS/octanol biphasic system exhibited a one-week release profile, and the released estradiol was fully active on HeLa ERE-luciferase ERα cells. The hybrid microparticles were cytocompatible during preliminary tests on NIH 3T3 fibroblasts (ISO 10993-5 standard) and they were fully biocompatible after subcutaneous injection on mice (ISO 10993-6 standard) underlining their high potential as a safe and long-acting subcutaneous drug delivery system.