SPARC-Targeted ZnS/BSA Nanoparticles For Multi-Mechanistic Mitigation of Early Brain Injury after Subarachnoid Hemorrhage.
Liu Xishu, Wang Lina, Li Chen, Chen Yucheng, Yang Jipeng, Cheng Hongyang, Yang Yue, Wang Wei, Liu Hongjiang, Wang Yupeng, Sun Xiaofeng
Abstract
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.
Key Findings
- SPARC is significantly upregulated in human and rat SAH brains, enabling targeted delivery of ZnS/BSA nanoparticles.
- ZnS/BSA nanoparticles release Zn2+ and H2S, which mitigate cerebral vasospasm and activate NRF2/HO-1 pathway to scavenge reactive oxygen/nitrogen species.
- The nanoparticles inhibit inflammatory signaling, microglial pyroptosis and apoptosis, preserve blood-brain barrier integrity, and improve neurological outcomes in a rat SAH model.
Clinical Significance
This study presents a targeted nanotherapeutic approach that addresses multiple injury pathways in early brain injury after subarachnoid hemorrhage, offering improved neuroprotection and functional recovery compared to existing treatments.
Citation
Liu Xishu, Wang Lina, Li Chenet al.. SPARC-Targeted ZnS/BSA Nanoparticles For Multi-Mechanistic Mitigation of Early Brain Injury after Subarachnoid Hemorrhage. ACS applied materials & interfaces. 2026-Sep-07.