Engineered Bio-Navigated Nanobubbles Mediating Xenon Neuroprotection and Neutrophil-Trojan Inflammation Regulation for Sequential Stroke Therapy

A key challenge in stroke therapy is overcoming multiple biological barriers in the brain and coordinating between neurovascular units. Cell membrane–based biomimetic carriers offer an approach for bio-navigated drug delivery; however, the modulation of their structure and function remains challenging. Herein, an engineering strategy for the bidirectional regulation of neutrophil-biomimetic xenon nanobubbles (Xe-EBs) is proposed for the multistage sequential treatment of stroke. By adjusting the proteins/lipids ratio through inflammatory activation (positive) and synthetic phospholipids hybridization (negative), the surface tension of membranes was regulated to obtain Xe-EBs with sizes of 563 ± 31, 263 ± 15, and 172 ± 8 nm. Membrane assembly was further modulated to form protein-enriched domains, which exhibited an enhanced inflammatory response similar to the upregulation of proteins. Activated neutrophil-Trojan Xe-EBs can target the inflamed endothelium and penetrate the blood–brain barrier for acute xenon neuroprotection and real-time recanalization. After uptake by activated microglia, the subacute inflammatory microenvironment is reshaped by reprogramming microglia M1–M2 polarization. In vivo and gene transcriptome analyses confirmed the efficacy and sequential mechanisms of stroke treatment. This study provides a paradigm for the modulation of biomimetic nanocarriers and a proof-of-concept for neutrophil-navigated sequential treatment for stroke.