Today, different therapeutic approaches are being developed because of the increased risk of colorectal cancer. In this context, we synthesized organic/inorganic hybrid nanoparticles using dextran (Dex) and dextran aldehyde (Dex-CHO) as organic polymers for the coating of inorganic silica aerogels. These Dex and Dex-CHO coated silica aerogels served as enzyme-triggered and colon targeted 5-Fluorouracil (5-FU) delivery systems. To improve the efficiency of drug loading and Dex/Dex-CHO coating, the surface of the silica aerogel was functionalized with 3-(aminopropyl)triethoxysilane (APTES). Enzyme-responsive drug release studies were performed with dextranase enzyme in simulated colonic fluid and cytotoxicity of aerogels on the colorectal adenocarcinoma cell line (Caco-2) were investigated by MTT assay. It was demonstrated that the release of 5-FU from Dex and Dex-CHO coated silica aerogels in simulated gastric and intestinal fluids was 1.7% and 3.4%, respectively, while the amount of 5-FU released from uncoated silica aerogels in these media was 86.4%. On the other hand, in the dextranase containing colonic medium 5-FU release in 12 h, straight after degradation of dextran by dextranase, was 24% and 13.4% from Dex and Dex-CHO coated silica aerogels, respectively. MTT assay results of unmodified, amine-modified, Dex and Dex-CHO coated silica aerogels did not show any significant cytotoxic effect on Caco-2 cells. However, MTT assay results of 5-FU loaded silica aerogels (unmodified, amine-modified, Dex and Dex-CHO coated) showed a decrease in the viability of Caco-2 cells. These results demonstrate that Dex and Dex-CHO coated silica aerogels are biocompatible nanoparticles that are not affected by the upper gastrointestinal regions and are powerful enzyme-triggered drug delivery systems for drug targeting to the colon area.