Targeted Retention of Cationic Liposomes at the Inflamed Blood–Brain Barrier by Incorporating Mesenchymal Stem Cell Membrane

ABSTRACT Blood–brain barrier (BBB) disruption is found in many acute and chronic inflammatory encephalopathies. Timely restoration of BBB integrity is essential for controlling disease progression, especially in ischemic stroke. While various brain‐targeting strategies have been developed, achieving precise BBB‐targeting and sustained retention at the BBB to enable faster and more effective repair remains a significant challenge. In this study, a biomimetic strategy is developed to enhance inflamed BBB‐targeting gene delivery using cationic hybrid nanovesicles derived from mesenchymal stem cell (MSC) membranes, named P(ML). The combined contributions of the positive surface charge and the biological targeting capability inherent to MSC membranes enable the precise inflamed BBB‐targeting of P(ML). In vitro and in vivo studies demonstrated that P(ML) efficiently accumulated in ischemic brain regions, and exhibited precise retention at inflamed BBB, rather than a diffuse distribution within the whole brain. Additionally, P(ML) showed efficient nucleic acid delivery capability. When loaded with siRNA targeting p66 ^Shc , a protein involved in endothelial dysfunction, P(ML) exhibited significant protective effects on the injured BBB in animal models. This biomimetic P(ML) nanocarrier platform represents a promising strategy for inflamed BBB‐targeting gene delivery, offering potential therapeutic applications for ischemic stroke and other BBB‐related disorders.