Anti-neuroinflammatory agent rhein lysinate-based self-assembled injectable hydrogel loaded with ZL006 for promoting post-stroke functional recovery.

The therapeutic agent-based self-assembled hydrogel is gaining interest for biomedical applications, because it overcomes the poor biodegradability and low therapeutic agent loading of conventional polymer gelator-based hydrogel. Here, we present rhein lysinate (RHL), a therapeutic agent that self-assembles to form a stable hydrogel through the π-π stacking and hydrogen bonding interactions, while also exerting anti-neuroinflammatory effect. As a small molecular hydrogelator, RHL has significantly improved water solubility and enhanced self-assembly and gelation capabilities compared to the natural anthraquinone rhein. The relaxed gel-forming conditions enhance the practical application potential of self-assembled hydrogel of RHL (RHL gel). The RHL gel can be loaded with the bioactive agents such as 5-Fluorouracil, temozolomide, edaravone, and ZL006, mainly based on efficient stacking between aromatic rings in the bioactive agents and anthraquinone rings in the hydrogel network structure. The pre-gelled RHL gel and ZL006-loaded RHL gel (ZL006-RHL gel) exhibit shear-thinning behavior, flowing like a liquid under high shear stress during injection. Once this shear stress is removal within the body, they rapidly recover to the initial solid-like state. When a single dose of ZL006-RHL gel is administrated to stroke cavity in the subacute phase of stroke, RHL gel matrix effectively reduces post-stroke neuroinflammation, creates a favorable environment for ZL006 to enhance neuroplasticity, and confers a sustained and stable action to ZL006, leading to a long-lasting improvement of motor performance. This study may provide a valuable strategy for therapeutic intervention to promote post-stroke functional recovery, for which there are no clinically available drugs.