Engineering chirality-dependent nanomedicines for neuroprotection by synergistic PANoptosis attenuation in ischemic stroke.

Abstract

Despite substantial breakthroughs in acute care, ischemic stroke remains a pressing, unresolved crisis in clinical practice and public health. Current therapies, which primarily depend on early revascularization, provide limited protection against the complex secondary injury mechanisms following ischemia, underscoring an urgent need for transformative solutions. In this study, we propose a chirality-dependent manganese carbon nanodot species (chiral MnCs) platform with paramagnetic MnCs cores functionalized with chiral penicillamine. These nanostructures perform dual roles, serving as T₁-weighted magnetic resonance imaging (MRI) contrast agents and reactive oxygen species scavengers. Especially, the chiral surface of MnCs enables stereoselective biological interactions, facilitating targeted accumulation in inflamed post-stroke brain regions. Notably, D-MnCs exhibit enhanced cellular uptake and superior therapeutic efficacy after crossing the blood-brain barrier. In vitro and in vivo experiments demonstrate that chiral MnCs significantly mitigate oxidative stress and aberrant microglial activation. More importantly, they effectively attenuate apoptosis, pyroptosis and necroptosis, the key components of PANoptosis, thereby reducing neuroinflammation and improving sensorimotor and cognitive recovery in mice with transient middle cerebral artery occlusion. This work develops a stereoselective, MRI-trackable nanoplatform that enables multi-mechanistic intervention in ischemic stroke, presenting an efficient strategy for precise neuroprotection and functional restoration.