Targeting the Immune-Neurovascular Interface to Ameliorate Pericyte Dysfunction with a Multifunctional Peptide–Drug Conjugate Nanoprodrug for Multiple Sclerosis Therapy

Abstract 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.