thermogelling hydrogel allowed to maintain in situ the enzyme activity ensuring efficient metabolization of a β-gal-sensitive prodrug (i.e., 5-FU-β-gal), administered in close proximity to the hydrogel. Then, the prodrug diffused within the matrix while the activated molecule diffused outward, resulting in a prolonged antitumor effect up to 14 days after a single administration. Sustained delivery of macromolecules from hybrid hydrogels has also been beneficial for regenerative applications. For example, growth factors-loaded nanogels embedded in Gel hydrogel, allowed for the regeneration of urethral muscle and robust recovery of the biological function when injected into the urethral wall in an incontinent animal model. Similarly, a VEGF-mimetic peptide was encapsulated in liposomes subsequently incorporated into a GelMA hydrogel and then, the hybrid hydrogel was injected at the site of peripheral nerve injury. The gradual release of the drug not only promoted neoangiogenesis and fostered the necessary vascularization for a regenerative environment, but also contributed to the polarization of macrophages toward an M2-like phenotype in vivo. This immune modulation, likely initiated by increased vascularization, created a positive feedback loop and altogether these processes resulted in a beneficial impact on nerve regeneration. In another context, namely bone formation and fracture healing, a significant benefit arose from in situ administration and tissue-specific localization of siRNA/NPs complexes embedded in a PEGbased hydrogel. This approach offered prolonged release over 30 days, reducing the required dose and minimizing off-target effects. Prolonged drug release was also suitable for triggering cell recruitment and differentiation.