A Self-Assembling Nanomodulator for Synergistic Therapy of Intracerebral Hemorrhage.

Introduction: Intracerebral hemorrhage (ICH) has high mortality and morbidity due to a complex secondary injury phase driven by oxidative stress and excessive inflammation. Given the limited efficacy of singularly-targeted therapies, there is a pressing need for novel therapeutic strategies capable of simultaneously modulating multiple aspects of this pathophysiological network. Methods: We developed a self-assembled nanomodulator, namely TNF@Gin: Targeted Nano Flower loaded with Ginkgetin (TNF@Gin), by fabricating Ginkgetin-loaded Nano Flowers via Rolling Circle Amplification (RCA). The therapeutic efficacy and mechanisms were systematically evaluated in microglial cells, hippocampal neuronal cells, and an ICH mouse model. Results: TNF@Gin demonstrated a synergistic regulatory effect by scavenging toxic reactive oxygen species, stimulating the polarization of microglia to the anti-inflammatory M2 phenotype, and inhibiting ferroptosis in hippocampal cells via the Nrf2/GPX4 pathway. In a mouse model of ICH, intravenous administration of TNF@Gin effectively alleviated brain hemorrhage and mitigated ICH-induced behavioral deficits. Conclusion: The nanomodulator TNF@Gin we developed is a safe and highly effective therapeutic agent for ICH synergistic therapy. To the best of our knowledge, this study represents the first RCA-based drug delivery system for ICH synergistic treatment, offering a novel and promising therapeutic strategy that synergistically targets inflammation and ferroptosis.