Rocket-Inspired Sequentially Targeted Nanotherapeutics for Mitochondrial Regulation and Inflammatory Reprogramming in...

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.