Liposomes containing nanogels (liponanogels) were fabricated by sonicating heparin-Pluronic (HP) nanogels with pegylated lipids for ribonuclease (RNase) delivery. Liponanogels with an average diameter of 316 nm were obtained and their spherical morphology was elucidated by atomic force microscopy (AFM). Confocal laser scanning microscopy (CLSM) revealed the core-shell structure of the liponanogels using two different fluorescent dyes, showing that HP nanogels were localized in the core of the liposomes. Interestingly, the hybridization of these two systems remedies the drawbacks of each system while they hold their strengths called “WIN-WIN effect”. When HP nanogels were used to encapsulate RNase in liponanogels, the loading of RNase was almost doubled as compared with the loading in liposomes without nanogels. Due to the presence of a lipid bilayer on the nanogels, the release of RNase was prolonged over 4 days whereas it was much faster (82% after 21 h) for bare HP nanogels. The cytotoxicity of the RNase-loaded liponanogels was much higher than that of free RNase because of the endocytic cellular uptake of the particles. We believe that these hybrid liponanogel systems can potentially be utilized for the hereditary diseases and targeted cancer therapy since they can efficiently load RNases and sustainly release in target cells.