Chloroplast-Inspired Nanoassemblies for Ischemic Stroke Therapy: Cross-Kingdom Recoupling with Mitochondrial Metabolism

Ischemic stroke (IS) features a dynamic collapse of neuronal mitochondrial metabolism. Current therapies fail to effectively address the sequential metabolic failures: ischemia disrupts the tricarboxylic acid cycle via substrate deprivation, while reperfusion impairs oxidative phosphorylation through ROS bursts. Inspired by the endosymbiotic metabolic loop between chloroplasts and mitochondria, we constructed a chloroplast-inspired nanoassembly via a membrane self-assembly strategy. This system compartmentalizes an energy module (nanothylakoids) and a catalytic module (CO₂-fixing nanocatalysts) within a light-harvesting module (upconversion nanoparticles-functionalized platelet membrane nanomotors), mimicking natural chloroplast architecture and replicating its full "phototaxis, energy supply, and carbon fixation" functionality. Under near-infrared light, the light-harvesting module first achieves phototactic penetration through thrombi and the blood-brain barrier, enabling progressive targeting to damaged neurons. After entering the cell, the energy module generates O₂/ATP/NADPH to reboot mitochondrial oxygen-carbon metabolism, while metabolic wastes (CO₂/lactate/ROS) are reciprocally supplied to the catalytic module for carbon fixation, subsequently converting into CO to further activate oxidative phosphorylation. This process ultimately establishes a cross-kingdom oxygen-carbon metabolic loop for IS therapy. We further demonstrate the efficacy of the system in other ischemic models (myocardial and limb ischemia), showing its capacity for multimodal coordination in substrate supply and waste clearance to effectively remodel mitochondrial function in damaged cells, thereby providing a strategy for metabolic reprogramming in ischemic disease therapy.