Roy, S.; Siwakoti, U.; Alday, D.; Astete, C.; McElveen, E.; Sigdel, A.; Del Piero, F.; Sabliov, C.; Castagnola, E.; Cai, Q.

Delivering therapeutics to the brain remains one of the most persistent challenges in medicine, because the blood-brain barrier (BBB) excludes over 98% of small-molecule drugs and virtually all biologics from the central nervous system (CNS). We developed electrical BBB modulation (eBBB), an on-demand platform combining vascular-targeting poly-L-lactic acid nanoparticles with high-definition transcranial direct current stimulation to achieve spatially and temporally controlled BBB opening. eBBB produced localized, reversible increases in BBB permeability confined to the stimulated cortex, with the opening area tunable via electrode geometry. This transient window enhanced regional delivery of a small-molecule drug, full-length immunoglobulins, and adeno-associated viral vectors, which are cargo classes otherwise completely excluded by the intact BBB. Neurovascular unit architecture was preserved with no lasting histological damage. Integrating a biodegradable nanomaterial with a clinically evaluated stimulation technology, eBBB offers a programmable, minimally invasive strategy for regional CNS drug delivery across brain malignancies and neurological disorders.