Injectable and Self-Healing Multifunctional Nanocomposite Hydrogel with an All-in-One Strategy for Efficient Synergistic Photothermal−Sonodynamic−Chemodynamic−Chemotherapy of Pancreatic Cancer

Traditional pancreatic cancer treatment has long been severely hindered by the dense stromal matrix barrier, which drastically impedes the deep penetration of chemotherapy drugs and thus compromises therapeutic efficacy, leading to unsatisfactory clinical outcomes. An injectable and rapid self-healing hydrogel based on β-cyclodextrin (β-CD) and hydroxypropyl chitosan (HPCS) loading multifunctional nanoparticles was designed for efficient synergistic therapy. Specifically, aldehyde-modified β-CD (ACD) and HPCS were cross-linked via a dynamic Schiff base reaction between aldehyde and amino groups, endowing the resultant ACD-HPCS hydrogel with excellent injectability, rapid self-healing capacity, and good biocompatibility for in situ administration, allowing it to conformably fill the irregular tumor cavities after injection. An all-in-one strategy was employed to integrate Prussian blue nanoparticle (PB NP) photothermal agent, titanium hydride nanoparticle (TiH_<i>x</i> NP, <i>x</i> ≈ 2-4) sonosensitizer, manganese dioxide nanoparticle (MnO₂ NP) nanozymes that generate ROS and scavenge GSH, and the chemotherapeutic drug doxorubicin (DOX) within an ACD-HPCS hydrogel. The multifunctional NPs provide the combination of near-infrared (NIR)-induced photothermal therapy (PTT), ultrasonic (US)-excited sonodynamic therapy (SDT), and chemodynamic therapy (CDT). In addition, DOX serves as a chemotherapeutic agent to exert the effect of chemotherapy (CT). By directly injecting ACD-HPCS into pancreatic cancer tissues, the multifunctional hydrogel can effectively overcome the stromal matrix barrier and circumvent the limitations of single-modal therapy, boosting drug accumulation in tumors to realize a quadruple-modal synergistic treatment effect combining PTT, SDT, CDT, and CT. This integrated therapeutic system therefore offers a highly promising and efficient strategy for clinical pancreatic cancer treatment.