Hydrogels can be formed via physical entanglement, noncovalent interactions, and chemical cross-linking. By rational design at the molecular level, enhanced physicochemical properties, such as shear thinning, self-healing, and responsive capacities may be afforded to hydrogels. Of note, considerable efforts have been devoted to engineering stimuli-responsive hydrogels, [2] since their formation, degradation, multiscale shape, architecture, and functions can be easily and precisely manipulated via different physical, chemical, and biological signals in spatiotemporally controlled and/or programmed manners. In this aspect, different exogenous and endogenous bio-physicochemical triggers are generally utilized to precisely control hydrogel formation/ degradation, finely tune the mechanics of hydrogels, and dynamically modulate hydrogel microenvironment. [2d,3] Hydrogels responsive to temperature, light, electrical/magnetic fields, ultrasound, mechanical forces, pH, redox potentials, and biochemical agents have been extensively examined for on-demand therapeutic delivery of drugs and cells to treat different acute and chronic diseases, [3a,4] for which controlled release of molecular and cellular payloads is mainly achieved by triggering transitions between hydrogel and solution phases or hydrogels and solid states. Also, stimuli-responsive hydrogels have been Functional hydrogels responsive to physiological and pathological signals have extensive biomedical applications owing to their multiple advanced attributes. Herein, engineering of functional hydrogels is reported via transformable nanoparticles in response to the physiologically and pathologically acidic microenvironment. These nanoparticles are assembled by a multivalent hydrophobic, pH-responsive cyclodextrin host material and a multivalent hydrophilic guest macromolecule. Driven by protons, the pH-responsive host-guest nanoparticles can be transformed into hydrogel, resulting from proton-triggered hydrolysis of the host material, generation of a hydrophilic multivalent host compound, and simultaneously enhanced inclusion interactions between host and guest molecules. By in situ forming a hydrogel barrier, the orally delivered transformable nanoparticles protect mice from ethanol-or drug-induced gastric injury. In addition, this type of nanoparticles can serve as responsive and transformable nanovehicles for therapeutic agents to achieve triggerable and sustained drug delivery, thereby effectively treating typical inflammatory diseases, including periodontitis and arthritis in rats. With combined advantages of nanoparticles and hydrogels, together with their good in vivo safety, the engineered transformable nanoparticles hold great promise in tissue injury protection and site-specific/local delivery of molecular and cellular therapeutic agents.