Thermoresponsive Injectable Self-Healing Hydrogel Loaded with Self-Regenerating Photothermal Agent for Synergistic...

Pancreatic ductal adenocarcinoma is highly malignant with poor prognosis. Its dense tumor microenvironment severely limits the efficacy of conventional chemotherapy and causes severe side-effects. Herein, we adopt the established Schiff-base crosslinked thermoresponsive injectable self-healing poly(2-(2-methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate-co-aldehyde 2-hydroxyethyl methacrylate)/carboxymethyl chitosan (APMOH/CMCS) hydrogel as the delivery scaffold. By regulating monomer composition, the volume phase transition temperature (T_VPT) of the hydrogel was tuned to around 43 °C to match the therapeutic temperature requirement. Subsequently, copper-metal organic framework (Cu-MOF) nanoparticles co-loaded with 2,2'-azobis(2-methylimidazoline) dihydrochloride (AIPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) cationic radicals (ABTS·⁺) (denoted as AB@Cu-MOF) were uniformly incorporated into the hydrogel network. Under near-infrared (NIR) irradiation, ABTS·⁺ acts as a photothermal agent to generate hyperthermia for tumor ablation; the elevated temperature further activates AIPH to produce alkyl radicals, which can oxidize inactivated ABTS back to ABTS·⁺ and construct a sustainable photothermal therapy-thermodynamic therapy (PTT-TDT) circulation. Meanwhile, Cu-MOF can consume intracellular glutathione (GSH) to protect active components from deactivation and initiate chemodynamic therapy (CDT) via Fenton-like reactions to produce toxic reactive oxygen species. Benefiting from the thermoresponsive characteristic, the hydrogel undergoes volume shrinkage upon heating, achieving NIR-triggered on-demand drug release with a cumulative release rate of 81.1%. In vitro and in vivo experiments verified that this integrated platform realizes remarkable triple synergistic efficacy of PTT, TDT, and CDT. The tumor volume of the treatment group was merely 13.3% of the control group, and the system also exhibited excellent biocompatibility. Collectively, it offers a feasible and promising intelligent platform for precise local treatment of pancreatic cancer.