Implantable piezocatalytic enzyme hydrogel re-engineers metabolic reprogramming for ischemic stroke therapy

Internal wireless electric stimulation (ES) based on piezoelectric materials with ultrasound (US) stimulation has emerged as a promising noninvasive strategy of tissue regeneration. However, due to poor electric field generation and their inherent ability to generate reactive oxygen species (ROS), piezoelectric materials have few been explored for the treatment of ROS related ischemic stroke (IS). Based on these properties, we design an intracerebrally injectable thermosensitive hydrogel (US+BCGTs@TSG) utilizing US-activated piezoelectric heterojunction known as BCGTs composed of barium titanate (BaTiO₃, BTO), cerium oxide (CeO₂), and graphene quantum dots (GQDs) for treating IS. Compared with conventional drug intravenous administration, in situ intracerebral injection of thermosensitive US+BCGTs@TSG can rapidly form a gel-like structure at body temperature, allowing for the direct delivery of therapeutic agents to the infarcted area. Following US, BCGTs target and repair mitochondria, inhibiting the occurrence of anaerobic metabolism. The combination of CeO₂ and GQDs facilitates electron transfer while also suppresses the generation of ROS from the piezoelectric materials. As a result, US+BCGTs@TSG contributes to a synergistic neuroprotective therapy and significantly reduces IS mediated neurodysfunction and depressive disorder.