Smart Sol‐Gel Hydrogels for Disease‐Targeted Therapeutics: Molecular Design and Biomedical Translation

ABSTRACT Stimuli‐responsive sol‐gel hydrogels constitute adaptive biomaterial platforms that couple therapeutic responses with disease‐specific biochemical parameters. This review examines reversible sol‐gel transitions actuated by pathological microenvironmental stimuli manifesting as biochemical and physicochemical cues, including localized hyperthermia, pH gradients, enzymatic activity, redox imbalance, ionic dysregulation, and inflammatory mediators, for spatiotemporally controlled drug delivery in chronic wounds, autoimmune disorders, metabolic diseases, and cancer. We establish correlations between disease‐characteristic biochemical landscapes and rationally designed transition mechanisms through analysis of pH‐responsive dynamic covalent chemistries, thermoresponsive phase transitions, analyte‐triggered network reorganization, and ionic strength‐mediated crosslinking. Translational implementations include glucose‐responsive insulin delivery, bacteria‐activated antimicrobial platforms, and tumor microenvironment‐targeted chemotherapeutic release. In particular, academic‐to‐commercial translation through pH‐responsive dermatological formulations and enzyme‐mediated biologic delivery technologies illustrates clinical implementation pathways. We evaluate emerging multi‐stimuli‐responsive designs and electronically integrated platforms, providing frameworks for engineering sol‐gel hydrogels as disease‐responsive therapeutic systems.