Injectable thermosensitive hydrogel embedding lignin-modified PLGA microspheres enables sustained lidocaine release and prolonged neuromodulation.

Malignant ventricular arrhythmias (MVA) post myocardial infarction (MI) is a leading cause of sudden death in affected patients. Hyperactivation of the sympathetic nervous system plays a crucial role in the onset and persistence of MVA after MI. While percutaneous stellate ganglion block with local anesthetics is an effective minimally invasive approach for transient MVA attenuation, achieving prolonged sympathetic blockade remains challenging. This study developed a novel injectable thermosensitive hydrogel-lignin-microsphere system for the sustained release of lidocaine (Gel-LMS Lido), aiming at long-term suppression of sympathetic nerve activity. Lignin-modified PLGA microspheres were used as the drug carrier, encapsulating lidocaine for sustained release. These microspheres were incorporated into a PLGA-PEG-PLGA hydrogel matrix, making up a triple-release system. The designed hydrogel-microsphere system demonstrated excellent injectability, controlled drug release profiles, prolonged pharmacological efficacy, robust in situ stability, and biocompatibility. In a rat MI model induced by left anterior descending coronary ligation, the materials were injected near the cervical stellate ganglion. Up to 2 weeks post-infarction, the sympathetic nerve activity was continuously suppressed and both the incidence and the duration of MVA were notably reduced in the Gel-LMS Lido group. Moreover, the Gel-LMS Lido was successfully extended to the treatment of sciatica, delivering a single injection with therapeutic effects lasting up to one week, highlighting the broad potential of present system for peripheral neuromodulation. In summary, this study is the first to demonstrate the use of a tailored Gel-LMS Lido triple-release system for cardiac neural modulation, significantly enhancing therapeutic outcomes in ischemic ventricular arrhythmias.