Abstract
Even after successful revascularization in acute ischemic stroke, some patients still develop secondary neuronal damage and functional impairment, known as cerebral ischemia-reperfusion injury (CIRI). The complex pathophysiological cascade within CIRI limits the efficacy of current single-target therapies in clinical practice. To address this, this study innovatively constructs a multifunctional brain-targeted nanoplatform (RFP) designed to synergistically intervene in the multiple pathological pathways of CIRI. This platform co-delivers Pt-based MXene nanozymes (Pt-Ti(3)C(2)) with SOD/CAT-like activity and the ferroptosis-specific inhibitor (Fer-1), enabling targeted delivery to the cerebral ischemic region via surface-modified cRGD peptides. The Pt-Ti(3)C(2) nanozyme core within the RFP exhibits SOD/CAT-like enzymatic activity, efficiently scavenging multiple ROS to inhibit oxidative stress. Meanwhile, Fer-1 embedded within the lipid bilayer suppresses lipid peroxidation, thereby blocking ferroptosis. Their synergistic action further mitigates neuroinflammation by suppressing pathological glial activation. In vivo and in vitro studies have demonstrated that RFP exhibits outstanding specific targeting efficacy and significant neuroprotective effects. Multi-omics analysis reveals that RFP exerts multi-effect therapy by synergistically suppressing oxidative stress and ferroptosis, maintaining mitochondrial homeostasis, and modulating inflammatory networks. This multifunctional nanotherapeutic strategy represents a shift from single-target treatment to multi-mechanism synergy, offering a novel approach to overcome CIRI therapeutic challenges.