Hitchhiking calvaria immune cells to bypass BBB for CNS drug delivery through transcranial nanoparticle microinjection

Bypassing blood brain barrier (BBB) remains a daunting challenge for drug delivery to the central nervous system (CNS). The recently discovered microscale ossified vascular channels connecting the skull bone marrow and the brain parenchyma may provide a direct brain entryway bypassing BBB, which may revolutionize CNS drug delivery. In this study, we demonstrated a nanoparticle transcranial microinjection strategy that hitchhikes bone marrow cells, which exhibit tropism for CNS lesions, to bypass BBB for CNS drug delivery. We have developed minimally invasive cranial drilling and microinjection techniques and validated the feasibility of the new pathway for CNS drug delivery. Through extensive experimental studies, we found that the nanoparticles injected into the skull bone marrow could construct a large number of drug-loaded immune cell microrobots in vivo. Following LPS-induced neuroinflammation or stroke induction, a significant increase in these microrobots was observed travelling through the microchannels and accumulating in the brain parenchyma. These results demonstrated the great potential of transcranial administration through the skull-meninge shortcuts and hitchhiking calvaria immune cells to bypass BBB for CNS drug delivery.