Abstract

Secondary neuroinflammation is a major driver of progressive damage after traumatic brain injury (TBI), yet pharmacological interventions are limited by poor drug accumulation in the injured brain. Here, we report tiered-targeting liposomal nanoparticles (TTL-NPs) for the precise delivery of the pyroptosis inhibitor disulfiram (DSF). Cloaked with endothelial cell membranes, TTL-NPs exploit homotypic interactions to improve BBB penetration. A hierarchically engineered peptide enables sequential delivery: nanoparticles first hitchhike neutrophils in peripheral blood via elastase binding and subsequently expose a neuronal targeting peptide (Tet1) after matrix metalloproteinase cleavage within the inflamed milieu, thereby detaching from the neutrophils and secondary targeting to neurons. In a murine TBI model, TTL-NPs enhanced DSF accumulation at the lesion sites, suppressed pyroptosis, preserved BBB integrity, alleviated neuroinflammation, and promoted cognitive recovery. This work integrates biomimetic camouflage with inflammation-responsive tiered targeting to achieve spatiotemporal control of pyroptosis inhibition, offering a promising strategy for TBI therapy and other central nervous system diseases.