Dysregulation of mevalonate pathway, an essential metabolic route involving coenzyme A (CoASH) and cholesterol, contributes significantly to escalating cartilage degradation. Existing treatments rely on the simvastatin delivery <i>via</i> tunable sol-gel transition mechanisms of injectable hydrogel. However, those methods suffer from lack of controllable drug release by selective phase transition under distinct disease microenvironment. Herein, we developed an aberrant lipid metabolism microenvironment-activated phase transition (normal condition: gel-gel, abnormal condition: gel-sol) with targeted drug release for synergistic treatment of osteoarthritis (OA). Naked-eye diagnosis and therapy of OA through cholesterol downregulation using an injectable hydrogel were based on the simvastatin-loaded nanoparticles embedded in hexanoyl glycol chitosan (HGC-SIM@PAA-MnO₂-cPDA or SIM gel). The interaction between highly expressed CoASH in OA and PAA-MnO₂ in SIM gel altered the hydrophobic-hydrophilic balance and gelation temperature, triggering the OA-sensitive gel-sol transformation. Naked-eye gel-sol transformation was observed after incubating SIM gel with OA chondrocyte models, including acetyl-CoA-induced wild-type (WT + CoA), <i>NudT7</i> ^<i>-/-</i> knockout (N7KO), and <i>Acot12</i> ^<i>-/-</i> knockout (A12KO). Because of the simvastatin release after gel-sol transition, OA-related enzymes and genes, including antioxidant enzymes (<i>Sod2</i>), cartilage degradation genes (<i>Adamts4</i>), and cholesterol synthesis-related enzymes (<i>Mvk</i>), were downregulated. <i>In vivo</i> studies revealed gel-sol transformation in destabilized medial meniscus of OA mice (DMM WT, N7KO, and A12KO) at 4-8 weeks post-injection, with significantly reduced cartilage degradation, demonstrating theragnostic capability of SIM gel. Thus, SIM gel offers a potential approach for future synergistic OA diagnosis and therapy.

Abstract A hypoxia‐specific diselenide‐crosslinked polymer dot (PD) nanoparticles‐based pyrogallol‐modified hydrogel (HS‐PD hydrogel) is developed for the facile monitoring of muscle ischemia recovery through multifaceted mechanical, electrical, and optical modulation. The ischemia environment‐sensitive conductive hydrogel exploits the specific cleavage of diselenide bonds induced by overexpressed reactive oxygen species (ROS), regulating fluorescence “on/off” activation, and subsequently modifies the microstructural morphology of the matrix. The HS‐PD hydrogel utilizes the oxidizing properties of pyrogallol to modulate its electroconductivity (ΔR decreased by ≈78.1%) and mechanophysical properties under normoxic conditions while enabling naked‐eye detection via visible color changes. Moreover, in vitro mechanophysical and electrical changes are evidenced by an increase in stretchability and compression modulus, alongside reduced electrical resistivity under normoxic conditions, as confirmed using C2C12 and 3T3‐L1 cell models. Additionally, in vitro gene expression analysis shows significant downregulation of SOD2 , Hif‐1α , and MuRF‐1 genes associated with muscle degradation, indicating enhanced ROS scavenging and potential oxygen normalization in ischemic regions. In vivo studies using a murine model of femoral artery ligation show a reduced inflammatory response, muscle fiber hypertrophy, and increased regenerative capacity in ischemic tissues. These findings highlight the potential of hydrogels in muscle regeneration and therapeutic applications.