A Biomimetic Multifunctional Nanoplatform with Precise Targeting-Penetration and Efficient Synergistic Therapy for...

Ischemic stroke poses a significant threat to public health, and its therapeutic efficacy is limited by blood-brain barrier permeability and multifactorial pathophysiology (such as oxidative stress and inflammation). In this study, a self-assembled metal-organic framework (Zn-DB) was decorated with CeO₂ nanoparticles to construct the CZB nanocomposite with antioxidative and antiapoptotic properties. The CZB-D-A multifunctional nanocomposite was developed by co-loading deferoxamine and an anti-C5a aptamer, and CZB-D-A was camouflaged with neutrophil-like membranes modified with RVG₂₉ to synthesize a biomimetic nanoplatform (RH@CZB-D-A) for precise targeting and penetration of the blood-brain barrier as well as immune evasion. Consequently, this nanoplatform precisely delivered therapeutic agents and released them better in the acidic lesion owing to its pH-acid response. It was designed to depolarize microglia from the destructive M1 phenotype to the protective M2 phenotype and alleviate ischemia-reperfusion injury by suppressing neuroinflammation, scavenging reactive oxygen species, and mitigating oxidative stress. Meanwhile, it synergistically promoted neuroprotection by multiple mechanisms of antioxidation, antiapoptosis, antiferroptosis, and anti-inflammation, both in vitro and in vivo. Additionally, administration of RH@CZB-D-A to MCAO mice not only enhanced neuronal regeneration but also improved neurological deficits and promoted spatial memory and learning ability. Therefore, this study could bring an alternative approach for developing promising therapeutic strategies against ischemic stroke for clinical applications.