Changes in the cerebral
microenvironment caused by acute
ischemic
stroke-reperfusion are the main obstacle to the recovery of neurological
function and an important cause of stroke recurrence after thrombolytic
therapy. The intracerebral microenvironment after ischemia-reperfusion
reduces the neuroplasticity of the penumbra and ultimately leads to
permanent neurological damage. To overcome this challenge, we developed
a triple-targeted self-assembled nanodelivery system, which combines
the neuroprotective drug rutin with hyaluronic acid through esterification
to form a conjugate, and then connected SS-31, a small peptide that
can penetrate the blood brain barrier and target mitochondria. Brain
targeting, CD44-mediated endocytosis, hyaluronidase 1-mediated degradation,
and the acidic environment synergistically promoted the enrichment
of nanoparticles and drug release in the injured area. Results demonstrate
that rutin has a high affinity for ACE2 receptors on the cell membrane
and can directly activate ACE2/Ang1-7 signaling, maintain neuroinflammation,
and promote penumbra angiogenesis and normal neovascularization. Importantly,
this delivery system enhanced the overall plasticity of the injured
area and significantly reduced neurological damage after stroke. The
relevant mechanism was expounded from the aspects of behavior, histology,
and molecular cytology. All results suggest that our delivery system
may be an effective and safe strategy for the treatment of acute ischemic
stroke-reperfusion injury.