Nanoparticles hijack calvarial immune cells for CNS drug delivery and stroke therapy.

The rapid accessibility of calvarial immune cells to the brain, in principle, may offer transformative opportunities for overcoming drug delivery barriers in central nervous system (CNS) disorders. Here, we hijacked calvarial immune cells using drug-loaded nanoparticles (NPs) and leveraged their unique migration mechanism through skull-meninges microchannels to bypass the blood-brain barrier (BBB) for CNS drug delivery. We constructed NP-loaded immune cells in situ via intracalvariosseous (ICO) injection, validated their prompt migration in response to CNS perturbation, and targeted therapeutic delivery to CNS lesions. Compared with conventional delivery approaches, this strategy achieved promising therapeutic efficacy in improving both short- and long-term outcomes in preclinical stroke models. Our prospective clinical trial further supports the translational feasibility of ICO immune access in treating malignant stroke. These findings establish skull-based delivery as a promising, clinically translatable route for CNS drug delivery and highlight immune-assisted transport as a potentially transformative strategy for improving therapeutic outcomes in neurological disorders.