Hydrogels that instruct cellular functions to e.g., restore damaged tissue while allowing minimally invasive application and therapeutic options are in high demand in regenerative medicine. Current hydrogel systems can rarely cover all highly attractive material properties required, e.g., high definition, biocompatibility, and self-healing. Considering these aspects, we investigate the guided assembly from molecule to macroscopic hydrogels and develop biohybrids as smart cell-instructive materials that can express dynamic soft tissue features. In this regard, inspired by Nature, we explore the combination of the stability of covalent bonds with dynamic behavior introduced by supramolecular chemistry to achieve a unique fusion of fundamental material characteristics, displaying adaptability, responsiveness, and interactivity: Biopolymer-derived backbones are combined with crosslinking units of either DNA, dynamic-coordinative interactions, or nanofiber-forming peptides yielding highly tunable 3D materials. In this regard, the programmability of supramolecular interactions achieves multifaceted structure formation, controlled delivery of bioactives to control cell population, or reversible crosslinking to facilitate gel injection minimizing damage to healthy tissue. The resulting hydrogels have a broad relevance to a variety of tissue engineering strategies as they demonstrate impressive material and biological properties like thixotropic behavior with fast and autonomous recovery as well as biocompatibility, and act as a platform opening various application scenarios.