Angiogenic Peptide Hydrogels Delivering Neuronal Differentiators for Treatment of Traumatic Brain Injury

Introduction：Traumatic brain injury (TBI) remains a major global cause of injury-related mortality and long-term neurological disability. However, significant advances in therapeutic strategies have been limited in recent years.

Methods：Herein, we developed a supramolecular hydrogel based on amphiphilically modified angiopoietin-1 (Ang-1) mimetic peptide. Retinoic acid (RA) was subsequently encapsulated into the hydrogel system to achieve sustained co-delivery of angiogenic and neurogenic cues. The formation and structural properties of the fabricated hydrogels were characterized by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy, while the critical micelle concentration (CMC) was determined by fluorescence spectroscopy with Nile red as a fluorescent probe. The biological performance of the hydrogel system was evaluated using cell scratch assays, tube formation assays, and in vitro RA release studies. To assess therapeutic efficacy, TBI was induced in mice via controlled cortical impact, followed by intracerebral injection of the RA-loaded hydrogels.

Results：In vitro assays demonstrated that the supramolecular hydrogels not only significantly promoted angiogenesis, but also enhanced the differentiation of neural stem cells into neurons. Furthermore, the Cell Counting Kit-8 (CCK-8) assay in a nerve cell co-culture system confirmed the neuroprotective effect. These findings were further corroborated in a mouse TBI model, where treatment with hydrogels significantly improved neuronal survival and reduced brain tissue loss.

Conclusions：In this study, supramolecular hydrogels loaded with RA were successfully constructed. These hydrogels enable the slow, continuous, and low-dose co-delivery of angiogenic growth factors and RA to local brain tissue, thereby demonstrating their potential for clinical translation in TBI treatment.