SPARC-Targeted ZnS/BSA Nanoparticles For Multi-Mechanistic Mitigation of Early Brain Injury after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) remains a devastating stroke subtype with high morbidity and mortality, largely due to complex early brain injury (EBI) within the first 72 h involving cerebral vasospasm (CVS), oxidative stress, and neuroinflammation. Existing therapies such as nimodipine offer limited protection and fail to address multiple injury pathways. Here, we report a SPARC-targeted albumin-based zinc sulfide nanoparticle (ZnS/BSA NPs) designed for lesion-specific delivery and multi-mechanistic therapy for SAH. We demonstrate that SPARC is significantly upregulated in both human and rat SAH brains, enabling active targeting of injured vasculature and crossing the blood-brain barrier (BBB). ZnS/BSA NPs exhibit good colloidal stability in serum-containing medium and pH-responsive release of Zn2+ and H2S. Mechanistically, Zn2+ suppresses Ca2+ influx/CaMKII activation to alleviate CVS; H2S activates NRF2/HO-1 to scavenge reactive oxygen/nitrogen species (RONS) and inhibits NF-κB/NLRP3 signaling to shift microglia from M1 to M2 polarization. Additionally, the NPs inhibit Caspase-1/GSDMD-mediated pyroptosis in microglia and suppress both Caspase-1/GSDMD-mediated pyroptosis and Bax/Caspase-3-mediated apoptosis in neurons, thereby preserving BBB integrity and reducing brain edema. In a rat SAH model, ZnS/BSA NPs significantly improved learning, memory, and motor function, outperforming nimodipine. This work highlights SPARC as a viable druggable target and represents a "targeted, multi-mechanistic" nanotherapeutic paradigm for EBI after SAH.