Targeting the Immune-Neurovascular Interface to Ameliorate Pericyte Dysfunction with a Multifunctional Peptide-Drug...

Pericyte dysfunction triggers blood-brain barrier (BBB) disruption and subsequent aberrant immune infiltration in multiple sclerosis (MS), yet targeted interventions remain lacking. Here, we engineered a dual-functional fusion peptide (VLC) for pericyte targeting and therapeutic intervention and subsequently conjugated it with luteolin to construct a peptide-drug conjugate (PDC)-based ROS-responsive nanoprodrug (VLC@Lut-NPs). This system significantly suppressed MMP-9 overactivation and mitigated neuroinflammation. To optimize the pharmacokinetic profile of the PDC nanotherapeutic, we adopted subcutaneous administration, achieving a prolonged circulation half-life and enhancing brain drug accumulation (AUCbrain) by 2.65-fold compared with intravenous injection. In two MS models, VLC@Lut-NPs restored pericyte homeostasis, reinforced BBB integrity, attenuated aberrant peripheral immune infiltration, and ultimately promoted myelin repair and regeneration. Notably, a once-every-other-day subcutaneous regimen outperformed daily intravenous administration. By bridging peripheral immunity and the neurovascular unit, this work identifies pericytes as a central regulatory node and establishes a pericyte-targeted PDC nanoplatform for durable MS treatment, highlighting its translational potential as a complementary strategy to conventional immunomodulatory approaches.