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Despite great therapeutic potential and development of a repertoire of delivery approaches addressing degradation and cellular uptake limitations, small interfering RNA (siRNA) exhibits poorly controlled tissue-specific localization. To overcome this hurdle, siRNA was complexed to nanoparticles (siRNA/NP) embedded within poly(ethylene glycol)-poly(lactic acid)-dimethacrylate (PEG-PLA-DM) hydrogels with the hypothesis that hydrolytic degradation of ester bonds within the PLA crosslinks would provide tunable, sustained siRNA/NP release. Hydrogels formed from macromers with increasing PLA repeats (e.g., 0 or non-degradable to 5 PLA repeats flanking PEG cores) and mixtures of nondegradable PEG-DM (0 PLA) and degradable PEG-PLA5-DM macromers were investigated. Hydrogels formed only with fully degradable crosslinks degraded rapidly over 6–14 days with limited control over siRNA/NP release. However, hydrogels formed with mixtures of nondegradable and 20%, 50%, and 100% degradable macromers resulted in siRNA/NP release over 3 to 28 days. Subsequently, gene silencing mediated by released siRNA/NP from 20% and 50% degradable hydrogels was sustained for ˜28 days. Furthermore, in vivo imaging showed that hydrogel degradation controlled siRNA/NP localization, with sustained siRNA/NP release from 0%, 20% and 50% degradable hydrogels over 28, 21, and 15 days. A model, which accounts for hydrogel degradation rate and siRNA/NP diffusion, was developed to enable rational design of siRNA/NP delivery depots. Overall, this study shows that siRNA/NP release can be sustained via encapsulation in hydrogels with tunable degradation kinetics and modeled for a priori design of delivery depots.