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, alpha- mangostin (alpha-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis while being loaded onto MSC-derived ApoVs as an antioxidant 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 alpha-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 alpha-M. The internal protein payloads of ApoVs, upon alpha-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.

Automated summary

This study presents a platform architecture that combines apoptosis induction, drug loading, and functionalized proteome regulation to create an apoptotic vesicle delivery system for ischemic stroke treatment. Alpha-mangostin (alpha-M) was loaded onto mesenchymal stem cell (MSC)-derived apoptotic vesicles as an antioxidant and anti-inflammatory agent, and a targeting peptide was modified on the surface of the vesicles. The engineered apoptotic vesicles targeted the injured ischemic brain and showed enhanced neuroprotective activity. The protein payloads of the vesicles were found to regulate immunological response, angiogenesis, and cell proliferation, contributing to their therapeutic effects. These findings provide a universal framework for creating apoptotic vesicle-based therapeutic drug delivery systems and demonstrate the potential of MSC-derived apoptotic vesicles for treating neural injury.