Chinese medicine-derived hydrogel attenuates traumatic brain injury by dual-antagonism of neuroinflammation and vasospasm

The malignant synergy between neuroinflammation and vasospasm is a core driving factor of secondary injury following traumatic brain injury (TBI), and self-assembling hydrogels for mechanical support and drug delivery have been extensively studied in therapeutic agents. Therefore, we utilized paeoniflorin (PF) and glycyrrhizic acid (GA) derived from Chinese medicine to synthesize a natural small-molecule self-assembling hydrogel (PG-gel, the PF/GA co-assembled hydrogel). Orchestrated via π-π stacking and hydrogen bonding interactions, as confirmed by X-ray Powder Diffraction, Fourier Transform Infrared Spectroscopy, ¹H Nuclear Magnetic Resonance and Mass Spectrometry. PG-gel exhibits a compliant mechanical modulus highly compatible with brain tissue modulus (~ 10 kPa) and achieving a cumulative drug release of 80% over 44 h. Mechanistically, PG-gel synergistically inhibits the dual pathological processes of neuroinflammation and vasospasm following TBI. Additionally, PG-gel demonstrates excellent biocompatibility and safety, with a hemolysis rate of less than 1%, meeting the application standards for green biomaterials. Taken together, this work not only describes a hydrogel that dually antagonizes neuroinflammation and vasospasm for effective intervention in TBI prognosis, but also provides new insights into strategies for neuroprotection and brain tissue repair.