Apigenin regulates CCR5/JAK1/STAT1/MMPs signaling to alleviate secondary brain injury after intracerebral hemorrhage and its enhanced delivery via targeted nanoparticles.

Intracerebral hemorrhage (ICH), a severe cerebrovascular disorder with high mortality, leads to secondary brain injury (SBI) primarily through neuroinflammation and blood-brain barrier (BBB) disruption. Among the pathological cascades, excessive activation of macrophages and the CCR5/JAK1/STAT1/MMPs signaling pathway play pivotal roles in amplifying neuronal damage. Apigenin (API), a natural flavonoid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic candidate to counteract these processes. In this study, we developed apigenin-loaded PLGA nanoparticles functionalized with DSPE-PEG2000-RVG29 and DSPE-PEG2000-folic acid (RVG/FA-NPs@API) to achieve targeted delivery to inflammatory macrophages and investigated their therapeutic effects against SBI after ICH. In a murine ICH model, API administration significantly improved neurological outcomes, reduced cerebral edema, suppressed neuronal apoptosis, and preserved BBB integrity. Mechanistically, API bound covalently to JAK1 at Cys1052, inhibiting its phosphorylation and subsequently downregulating the CCR5/JAK1/STAT1/MMPs cascade. Furthermore, RVG/FA-NPs@API demonstrated excellent stability, efficient brain-targeting, and superior biocompatibility, achieving enhanced therapeutic efficacy compared with free API. These findings highlight a novel strategy for targeted immunomodulation and provide translational insights into nanoparticle-assisted delivery of natural compounds for the treatment of ICH-induced SBI.