Reducing the complex extracellular matrices (ECM) to chemically defined polymer networks represents an attractive avenue for understanding and recapitulating the biology of the ECM. However, while lipids are also important components of ECM, it remains challenging to investigate lipids as a modular functionality in synthetic biomaterials, especially in a self-assembled network. In this study, in order to establish a modular amphiphilic system, lipid-modifications are introduced into a noncovalent hydrogel system cross-linked by peptide-polysaccharide interaction through conjugating fatty acids of different lengths to a peptide. The amphiphilic matrices can interact with hydrophobic drugs, thus enhance their loading efficiency and result in sustainable release. The physical hydrogel system can be used for encapsulating cells, while embedded mesenchymal stromal cells exhibit high viability and retain immunoregulatory activity. In addition, the material can also be used for gel-in-gel injection to model drug partitioning in 3D, as well as controlled fast gel degradation under an extremely mild condition using human serum albumin (HSA). This self-assembling modular system can provide a versatile toolbox to tailor synthetic polymers for engineering 3D models to study bioactive molecules, such as hydrophobic hormones and drugs as well as to develop injectable therapeutic materials.