Abstract

The treatment of intracerebral hemorrhage (ICH) remains highly challenging, primarily due to its dynamic and multifaceted pathologies, which create a hostile microenvironment at the lesion site characterized by a ROS-inflammation-glial scar feedback loop and severely impaired neural regeneration. Herein, a dynamic protein-polysaccharide hydrogel is designed, constructed by a visible light-induced thiol-disulfide exchange reaction as a general strategy, and integrated with a spatiotemporal controlled delivery of chondroitinase ABC (ChABC) and insulin-like growth factor-1 (IGF-1) loaded in mesoporous silica nanoparticles (MSNs). Thiolated gelatin and thiolated hyaluronan were chosen to formulate the hydrogel that mimics brain ECM providing structure support with cell adhesion, infiltration, and tunable degradability, but also presents anti-swelling and pro-coagulant capacities. Importantly, the thiol-disulfide chemistry endowed the hydrogel efficient ROS scavenging and ROS-responsive on-demand release of ChABC, while MSNs loading achieved a sustained release of IGF-1. In vitro studies, the hydrogel is shown to reduce cellular ROS, regulate anti-inflammation polarization of macrophages via the MAPK signaling pathway, and promote neural stem cells (NSCs) proliferation, migration, differentiation and endothelial angiogenesis. Moreover, in an ICH mouse model, the hydrogel is demonstrated not only to enable efficient tissue ROS scavenging, anti-inflammation polarization of microglial/macrophages, and dynamical self-adaptive reduction of glial scar, achieving microenvironment remodeling, but also to regulate behaviors of endogenous NSCs and enhance angiogenesis, providing neural regeneration. Consequently, these effects enhanced neurons and myelin repair, ultimately contributing to synergistic recovery of neurological function. Overall, this dynamic hydrogel represents a promising strategy for simultanously remodeling the lesion site's microenvironment and promoting neur