Ischemic
stroke is a leading cause of long-term disability and death worldwide.
Current drug delivery vehicles for the treatment of ischemic stroke
are less than satisfactory, in large part due to their short circulation
lives, lack of specific targeting to the ischemic site, and poor controllability
of drug release. In light of the upregulation of reactive oxygen species
(ROS) in the ischemic neuron, we herein developed a bioengineered
ROS-responsive nanocarrier for stroke-specific delivery of a neuroprotective
agent, NR2B9C, against ischemic brain damage. The nanocarrier is composed
of a dextran polymer core modified with ROS-responsive boronic ester
and a red blood cell (RBC) membrane shell with stroke homing peptide
(SHp) inserted. These targeted “core–shell” nanoparticles
(designated as SHp-RBC-NP) could thus have controlled release of NR2B9C
triggered by high intracellular ROS in ischemic neurons after homing
to ischemic brain tissues. The potential of the SHp-RBC-NP for ischemic
stroke therapy was systematically evaluated in vitro and in rat models of middle cerebral artery occlusion (MCAO). In vitro results showed that the SHp-RBC-NP had great protective
effects on glutamate-induced cytotoxicity in PC-12 cells. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) testing
further demonstrated that the bioengineered nanoparticles can drastically
prolong the systemic circulation of NR2B9C, enhance the active targeting
of the ischemic area in the MCAO rats, and reduce ischemic brain damage.