A hybrid hydrogel composed of solid lipid nanoparticles (LNPs) entrapped within chemically cross-linked carboxymethylcellulose (CMC) is developed to achieve localized and sustained release of lipophilic drugs. The analysis of LNP stability as well as the hydrogel swelling and mechanical properties confirm the successful incorporation of particles up to a concentration of 50% w/wCMC. The initial LNP release rate can be prolonged by increasing the particle diameter from 50 to 120 nm, while the amount of long-term release can be adjusted by tailoring the particle surface charge or the cross-linking density of the polymer. After 30 d, 58% of 50 nm diameter negatively charged LNPs escape from the matrix while only 17% of positively charged nanoparticles are released from materials with intermediate cross-linking density. A mathematical diffusion model based on Fick's second law is efficient to predict the diffusion of the particles from the hydrogels. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim