Methotrexate functionalized silica-gelatin hybrid aerogel (SGM) was synthesized by the sol–gel method and co-gelation. The drug methotrexate (MTX) is covalently linked to the collagen molecules of the hybrid aerogel backbone by amide-bond. The characteristic MTX content of the functionalized hybrid aerogel is ca. 6 wt% by the dry weight. The micronization of SGM aerogel in water yields cell sized ( d = 10–20 µm) particles. The cytotoxicity of these microparticles against tumor cell lines (SCC VII and HL-60) is unprecedentedly high, it is approximately equivalent to that of an equal dose of free (dissolved) MTX, as proved by in vitro experiments. Thus, the activity of MTX is intact after aerogel functionalization, and the mass specific cytotoxicity of SGM is high enough for medical applications. Drug release studies verified that MTX cannot be liberated from this drug delivery system solely by chemical hydrolysis, however, collagenase enzymatic activity releases MTX from the functionalized hybrid aerogel. The cytotoxicity of SGM towards various cancerous and non-cancerous cell lines correlates with the collagenase activities of cells. Therefore, conjugation with the hybrid aerogel provides a controlled release system for the antineoplastic agent MTX. The morphology of the delivery vehicle was chosen to adapt the size of cancer cells; thus the metastatic pathways of the tumor cells can get flooded.