The novel cellulose-based hybrid smart hydrogelsHydrogels have been identified as dynamic in the field of tissue engineeringTissue Engineering (TE) because of their impressive biocompatibilityBiocompatibility, robust mechanical propertiesMechanical properties, and capacity to adapt. Hydrogels designed for these tissue architectures are composed of nanoscale components and responsive polymers to achieve structural and biological properties that are relevant to the complexity of the tissue microenvironment. In this chapter, the current state of smart hydrogelsHydrogels based on cellulose hybrids covering the design of such hydrogels and functionalizationFunctionalization steps in connection with the application of resultant hydrogels on various types of tissues would be discussed. This chapter describes how alteration of biomaterial properties, multi-stimuli-responsiveStimuli-responsive hydrogelsHydrogels for tissue engineeringTissue Engineering (TE), and cellular response to the engineered matrix are explored to understand how these synthetic materials can be designed in a manner that resembles the natural tissue milieu and support regenerative medicineRegenerative medicine application. A focus has been made on composites of hydrogel/nanoparticlesNanoparticles, stimuli responsiveness, and bioactivityBioactivity for enhanced cell growth and differentiationDifferentiation to enhance clinical outcomes involvingSmart material tissue repair/regeneration applications.