Microfluidics‐Prepared Ultra‐small Biomimetic Nanovesicles for Brain Tumor Targeting

Blood-brain-barrier (BBB) serves as a fatal guard of the central nervous system as well as a formidable obstacle for the treatment of brain diseases such as brain tumors. Cell membrane-derived nanomedicines are promising drug carriers to achieve BBB-penetrating and brain lesion targeting. However, the challenge of precise size control of such nanomedicines has severely limited their therapeutic effect and clinical application in brain diseases. To address this problem, this work develops a microfluidic mixing platform that enables the fabrication of cell membrane-derived nanovesicles with precise controllability and tunability in particle size and component. Sub-100 nm macrophage plasma membrane-derived vesicles as small as 51 nm (nanoscale macrophage vesicles, NMVs), with a narrow size distribution (polydispersity index, PDI: 0.27) and a high drug loading rate (up to 89% for indocyanine green-loaded NMVs, NMVs@ICG (ICG is indocyanine green)), are achieved through a one-step process. Compared to beyond-100 nm macrophage cell membrane vesicles (general macrophage vesicles, GMVs) prepared via the traditional methods, the new NMVs exhibits rapid (within 1 h post-injection) and enhanced orthotopic glioma targeting (up to 78% enhancement), with no extra surface modification. This work demonstrates the great potential of such real-nanoscale cell membrane-derived nanomedicines in targeted brain tumor theranostics.