Rocket‐Inspired Sequentially Targeted Nanotherapeutics for Mitochondrial Regulation and Inflammatory Reprogramming in Ischemic Stroke

ABSTRACT Mitochondrial dysfunction causes inflammatory cascades in cerebral ischemia‐reperfusion injury (CIRI). However, precise pharmacological interventions are hindered by the restrictive blood‐brain barrier (BBB). Here, we report a neutrophil‐hitchhiking, biomimetic nanoplatform (NeuM@Mdivi‐1) with a “rocket‐inspired” sequential targeting strategy for restoring mitochondrial homeostasis. By co‐opting the innate chemotaxis of circulating neutrophils, NeuM@Mdivi‐1 effectively bypassed the BBB to infiltrate the ischemic penumbra. Within this pathological microenvironment, upregulated matrix metalloproteinase‐9 (MMP9) triggers surface transformation, exposing mitochondrial‐targeting peptides and enabling the precise intracellular release of the fission inhibitor Mdivi‐1. This spatiotemporal delivery approach effectively suppresses aberrant dynamin‐related protein 1 (Drp1)‐mediated fission, thereby silencing the Drp1/mtDNA/cGAS‐STING signaling axis and mitigating neuronal ferroptosis. NeuM@Mdivi‐1 preserves neuronal viability and reengineers the immune microenvironment by decoupling mitochondrial fragmentation from the inflammatory response, thereby establishing a sophisticated therapeutic paradigm for CIRI management.