Redox-modulating macrophage biohybrid nanoplatform for targeted RIPK1-PANoptosome suppression in ischemic stroke.

Abstract

Disruption of redox homeostasis during reperfusion triggers a complex and dynamic neuroinflammatory cascade in ischemic stroke, posing a major barrier to precision therapy. Although cellular therapies have emerged as a promising strategy, their clinical translation is hindered by the lack of tools capable of simultaneously tracking cell delivery and modulating pathological redox imbalance in vivo. Here, we report an MRI-trackable engineered macrophage-derived biohybrid nanoplatform that integrates the inflammation-homing capacity of macrophages, the imaging functionality of ultrasmall superparamagnetic iron oxide nanoparticles, and the redox-regulating activity of 2,2,6,6-tetramethylpiperidine-1-oxyl-doped lipids to restore local redox homeostasis. Leveraging their innate tropism toward inflamed tissue, the engineered macrophages selectively accumulate at sites of post-ischemic neuroinflammation. Concurrently, their intrinsic reactive oxygen species-scavenging capability alleviates oxidative stress, thereby suppressing a redox-dependent network of programmed cell death PANoptosis. In vivo ischemic stroke models demonstrate that this redox-modulating biohybrid nanoplatform significantly inhibits oxidative stress-induced PANoptosis, leading to enhanced neuronal survival and improved neurological recovery. Notably, the engineered macrophages function as both redox state imagers and active modulators, enabling real-time visualization and spatiotemporal regulation of redox dynamics within the ischemic brain. Collectively, this work establishes a precision theranostic strategy to disrupt the oxidative stress-PANoptosis axis and highlights a broadly applicable platform for the treatment of oxidative stress and inflammation associated diseases.