Tailored Apoptotic Vesicle Delivery Platform for Inflammatory Regulation and Tissue Repair to Ameliorate Ischemic Stroke

Apoptotic
vesicles (ApoVs) hold great promise for inflammatory
regulation and tissue repair. However, little effort has been dedicated
to developing ApoV-based drug delivery platforms, while the insufficient
targeting capability of ApoVs also limits their clinical applications.
This work presents a platform architecture that integrates apoptosis
induction, drug loading, and functionalized proteome regulation, followed
by targeting modification, enabling the creation of an apoptotic vesicle
delivery system to treat ischemic stroke. Briefly, α-mangostin
(α-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis
while being loaded onto MSC-derived ApoVs as an anti-oxidant and anti-inflammatory
agent for cerebral ischemia/​reperfusion injury. Matrix metalloproteinase
activatable cell-penetrating peptide (MAP), a microenvironment-responsive
targeting peptide, was modified on the surface of ApoVs to obtain
the MAP-functionalized α-M-loaded ApoVs. Such engineered ApoVs
targeted the injured ischemic brain after systemic injection and achieved
an enhanced neuroprotective activity due to the synergistic effect
of ApoVs and α-M. The internal protein payloads of ApoVs, upon
α-M activation, were found engaged in regulating immunological
response, angiogenesis, and cell proliferation, all of which contributed
to the therapeutic effects of ApoVs. The findings provide a universal
framework for creating ApoV-based therapeutic drug delivery systems
for the amelioration of inflammatory diseases and demonstrate the
potential of MSC-derived ApoVs to treat neural injury.