Simple SummarypH-responsive hydrogel microparticles have great potential as drug delivery systems of anti-cancer drugs. Here, we use microfluidics for the generation of asymmetric microgels as carriers for oral administration of 5-fluorouracil (5-FU) in colorectal cancer. Due to their anisotropic shape, they show increased on-demand loading of the drug. The pH-responsiveness is ensured by the presence of alginate methacrylate within the gel network and represents the key factor for 5-FU release at the targeted location. Empty, asymmetric microgels do not show cytotoxicity even at high concentration, while upon treatment with 5-FU loaded microparticles, the viability of tumor cells notably decreases confirming the efficacy of drug release at certain pH.AbstractIn the last 20 years, the development of stimuli-responsive drug delivery systems (DDS) has received great attention. Hydrogel microparticles represent one of the candidates with the most potential. However, if the role of the cross-linking method, polymer composition, and concentration on their performance as DDS has been well-studied, still, a lot needs to be explained regarding the effect caused by the morphology. To investigate this, herein, we report the fabrication of PEGDA–ALMA-based microgels with spherical and asymmetric shapes for 5-fluorouracil (5-FU) on-demand loading and in vitro pH-triggered release. Due to anisotropic properties, the asymmetric particles showed an increased drug adsorption and higher pH responsiveness, which in turn led to a higher desorption efficacy at the target pH environment, making them an ideal candidate for oral administration of 5-FU in colorectal cancer. The cytotoxicity of empty spherical microgels was higher than the cytotoxicity of empty asymmetric microgels, suggesting that the gel network’s mechanical proprieties of anisotropic particles were a better three-dimensional environment for the vital functions of cells. Upon treatment with drug-loaded microgels, the HeLa cells’ viability was lower after incubation with asymmetric particles, confirming a minor release of 5-FU from spherical particles.