TY  - JOUR
AU  - Yin, Yue
AU  - Li, Zixuan
AU  - Shu, Weijie
AU  - Liu, Hening
AU  - Wang, Zihan
AU  - Fu, Cong
AU  - Zhu, Yuanbo
AU  - Li, Xuejing
AU  - Zhang, Yi
AU  - Lv, Bei
AU  - Wang, Zixuan
AU  - Zhao, Qiaoqiao
AU  - Liu, Dan
AU  - Tang, Lu
AU  - Wang, Wei
TI  - Intranasal blood-brain barrier bypass enables sequential mitochondria-targeted bioengineered nanolamellar system for ischemic stroke therapy.
JO  - Nature Communications
VL  - 17
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2026-00080
SP  - 760
PY  - 2026
AB  - Mitochondrial damage constitutes the central pathological mechanism of cerebral ischemia-reperfusion (I/R) injury. Targeted delivery of antioxidants to mitochondria and the phenotype polarization of glial cells holds great promise for effective treatment. However, the blood-brain barrier (BBB) remains a major obstacle, causing insufficient drug accumulation in neuronal mitochondria. Here, we develop a bioengineered nanolamellar system (MM@BPPF) by coating microglia-mitochondria hybrid biomembrane onto black phosphorus nanosheets (BP NSs) loaded with polymetformin (PolyMet) and fingolimod hydrochloride (FTY720). Microglia membrane facilitates inflammation-directed targeting to the injured brain regions, while mitochondria membrane confers homotypic targeting to mitochondria. Meanwhile, BP NSs, PolyMet, and FTY720 act sequentially to restore mitochondrial function of neuronal cells and modulate microglial polarization. Intranasal administration enables MM@BPPF to bypass the BBB, substantially improving brain-targeting efficiency. This work not only offers an innovative sequential targeting strategy for mitigating I/R injury but also presents a potential paradigm for treating other central nervous system disorders.
KW  - Blood-Brain Barrier: metabolism
KW  - Blood-Brain Barrier: drug effects
KW  - Animals
KW  - Mitochondria: metabolism
KW  - Mitochondria: drug effects
KW  - Microglia: metabolism
KW  - Microglia: drug effects
KW  - Mice
KW  - Ischemic Stroke: drug therapy
KW  - Ischemic Stroke: metabolism
KW  - Ischemic Stroke: pathology
KW  - Administration, Intranasal
KW  - Fingolimod Hydrochloride: administration & dosage
KW  - Fingolimod Hydrochloride: pharmacology
KW  - Reperfusion Injury: drug therapy
KW  - Male
KW  - Mice, Inbred C57BL
KW  - Drug Delivery Systems: methods
KW  - Bioengineering
KW  - Neurons: drug effects
KW  - Neurons: metabolism
KW  - Disease Models, Animal
KW  - Brain: metabolism
KW  - Brain: drug effects
KW  - Fingolimod Hydrochloride (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41547891
DO  - DOI:10.1038/s41467-025-68024-5
UR  - https://pub.dzne.de/record/284045
ER  -