Injectable nanocomposite hydrogel for localized precision delivery of dexamethasone after traumatic brain injury: dual modulation of neuroinflammation and blood-brain barrier restoration
Bin Zhang, Miao Bai, Mengshi Yang, Yumei Wang, Xiyu Chen, Baiyun Liu, Guangzhi Shi
Abstract
BACKGROUND: Glucocorticoids (GCs) have been widely used in the treatment of severe traumatic brain injury (TBI) to inhibit neuroinflammation and alleviating brain edema and cannot be replaced by other drugs. However, their systemic application still faces many obstacles, such as the poor blood-brain-barrier (BBB) penetration and severe side effects. Therefore, new treatment strategy or compounds are urgently needed in clinic. METHODS: Herein, an injectable nanocomposite hydrogel is developed as a biofunctionalized delivery platform for intraoperative administration of dexamethasone (DEX) after TBI. By using a mice TBI model, the safety and efficacy of the nanohydrogels in treating BBB disruption, brain edema and nerve injury were evaluated after TBI. RESULTS: The hydrogel is composed of polysaccharide matrix (carboxymethyl chitosan and oxidized dextran) and mesoporous polydopamine (MPDA) nanoparticles loaded with DEX (MPDA@DEX@gel) that could realize in situ injection, self-assembly, a high DEX loading rate and sustained release around the lesion. The MPDA@DEX@gel exhibits excellent antibacterial and hemostatic properties, good biocompatibility and antioxidation, and self-healing capability in vitro. These in vitro and in vivo results show that local application of MPDA@DEX@gel not only alleviates brain edema, promotes neuronal survival, and improves neurological function by restoring the integrity of BBB and inhibiting neuroinflammation after TBI, but also effectively avoids the peripheral and central side effects. CONCLUSION: Our study provides a promising treatment strategy for the rational use of GCs in patients with severe TBI.