5-Fluorouracil (5-Fu) commonly use in the treatment of different kinds of cancer, but limited cellular uptake and death is still a problem. Herein, we report a simple process for the synthesis of pressure-sensitive nanogels that indicate to be appropriate in the delivery of 5-Fu. The hydrogels (Al-CD) prepare by crosslinking of alginate (Al) with modified beta Cyclodextrin (β-CD) as Crosslinker. Next, nanoparticles obtaine by an emulsification method. 5-Fu as model drug loades into the Al-CD nanogels easily by mixing it in aqueous solution with the nanoparticles. The results revealed that the Al-CD nanogels are cytocompatible. They have also a noticeable drug encapsulation (82.1 ±5.7%) while they can release (in vitro controlled) 5-Fu in conditions that imitate the intravascular pressure conditions. These nanogels can rapidly be taken up by HT-29 cells (a colon cell line). In addition, a higher 5-Fu intracellular accumulation and a significant cell death extension by apoptosis mechanism is notice when compare with free 5-Fu. Accordingly, the developed nanogels can be employe as an excellent candidate to overcome the inefficiency of 5-Fu in anticancer treatments and possibly can employe for further evaluation as a chemotherapical agent in applications beyond cancer. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 349-359, 2018.