Herein, the polysaccharide gelation was triggered by urine leading to the formation of a GG matrix with extended retention on the urothelium that facilitated the deep penetration of liposomes into the bladder wall. Stable hydrogel networks can also be formulated using hydroxypropyl methylcellulose (HPMC), which is a water-soluble synthetic derivative of the natural polysaccharide. Functionalization of HPMC with C12 chains enhanced its hydrophobicity resulting in a material capable of interacting effectively with dispersed poly(lactic acid) (PLA)-based NPs, thus forming a stable hybrid nanocomposite hydrogel with several potential applications in drug delivery. In general, these natural materials possess favorable properties, but their use in the formulation of hybrid hydrogels still faces some limitations. They include the need for modifications to improve performance, batch-to-batch variability, limited control on degradation rates and potential immunogenicity. Consequently, when using these materials, a careful evaluation, in order to guarantee both efficacy and safety, needs to be carried out.