Treatment
of cardiac arrest/cardiopulmonary resuscitation (CA/CPR)-induced
brain injury remains a challenging issue without viable therapeutic
options. Octanoic acid (OA), a lipid oil that is mainly metabolized
in the astrocytes of the brain, is a promising treatment for this
type of injury owing to its potential functions against oxidative
stress, apoptosis, inflammation, and ability to stabilize mitochondria.
However, the application of OA is strictly limited by its short half-life
and low available concentration in the target organ. Herein, based
on our previous research, an OA-based nanotherapy coated with a neutrophil
membrane highly expressing RVG29, RVG29-H-NPOA, was successfully
constructed by computer simulation-guided supramolecular assembly
of polyethylenimine and OA. The in vitro and in vivo experiments showed that RVG29-H-NPOA could
target and be distributed in the injured brain focus via the relay-targeted delivery mediated by RVG29-induced blood–brain
barrier (BBB) penetration and neutrophil membrane protein-induced
BBB binding and injury targeting. This results in enhancements of
the antioxidant, antiapoptotic, mitochondrial stability-promoting
and anti-inflammatory effects of OA and exhibited systematic alleviation
of astrocyte injury, neuronal damage, and inflammatory response in
the brain. Due to their systematic intervention in multiple pathological
processes, RVG29-H-NPOA significantly increased the 24
h survival rate of CA/CPR model rats from 40% to 100% and significantly
improved their neurological functions. Thus, RVG29-H-NPOA are expected to be a promising therapeutic for the treatment of
CA/CPR-induced brain injury.