A multi-target nano-therapy against cerebral ischemia/reperfusion injury via combinatorial inhibition of neuroinflammation and pyroptosis.

Authors

Wenchao Fu, Ayang Zhao, Bo Chen, Yu Feng, Hongliang Shen, Jietao Li, Xianzhang Zeng

Published in

Journal of materials chemistry. B. Jul 15, 2026. Epub Jul 15, 2026.

Abstract

Background & purpose: ischemic stroke reperfusion injury involves a vicious cycle of neuroinflammation, pyroptosis, and oxidative stress. Single-target therapies have limited efficacy. In this study, we aimed to develop an actively targeted, multi-drug combinatorial nano-platform for coordinated intervention against ischemia/reperfusion (I/R) injury. Methods: we synthesized CX3CL1-functionalized ZIF-8 nanoparticles co-loaded with disulfiram (DFL, a GSDMD-N pore inhibitor), paquinimod (PAQ, a TLR4/NF-κB inhibitor), and siNINJ1 (inhibiting membrane rupture). The nanoparticles were systematically characterized. Their neuroprotective effects and mechanisms were evaluated using a transient middle cerebral artery occlusion (tMCAO) mouse model and an oxygen-glucose deprivation/reoxygenation (OGD/R) co-culture model in vitro. Results: the nanoparticles exhibited pH-responsive release and active targeting to the ischemic penumbra. In vivo and in vitro results demonstrated that they synergistically inhibited the TLR4/NF-κB/NLRP3 signaling axis and pyroptosis execution (GSDMD, caspase-1), promoted microglial polarization towards the M2 phenotype, reduced pro-inflammatory cytokines (IL-6, TNF-α), and alleviated oxidative stress and neuronal apoptosis, ultimately leading to significantly reduced infarct volume and improved neurological recovery. Conclusion: we successfully developed an "active targeting-multi-drug synergy-cascade intervention" nano-therapeutic platform that effectively mitigates cerebral I/R injury through multi-pathway coordination, offering a novel combinatory strategy for ischemic stroke treatment.

PMID:
42455768
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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