Intracalvariosseous injection bypasses the blood-brain barrier as a novel drug delivery approach for pre-clinical and clinical trials in stroke

Central nervous system (CNS) accessibility constitutes a major hurdle for drug development to treat neurological diseases. Existing drug delivery methods rely integrity of the blood-brain barrier (BBB) for CNS penetration. Here we showed that the microchannels between the skull marrow and the dura mater could be harnessed for drug delivery by intracalvariosseous (ICO) injection. Drugs administered via ICO injection were found to reach cranial bone marrow-dura-perivascular space, and the injection procedure did not cause osteomyelitis or BBB damage. To validate this approach, we examined the efficacy of two neuroprotective agents, NA-1 and Y-3, via ICO injection in rat model of stroke and found that ICO injection increased drug accumulation in the brain compared to intravenous injection, reduced infarct area and alleviated neurological deficits. We subsequently conducted a clinical trial to assess the safety of ICO in acute ischemic stroke patients ( ClinicalTrials.gov identifier NCT05849805 ), showing that ICO injection was feasible and safe in humans and its therapeutic effects may be observed. Collectively, our study identifies that the microchannels between the skull bone marrow and the dura mater act as a new channel for CNS drug delivery to achieve high intracranial drug exposure in a short period of time. The safety of ICO injection makes it a promising route of drug administration for CNS diseases.