Biomimetic PB@PDA‐CA@Mem nanoplatform regulates oxidative stress and inflammatory microenvironment to enhance stroke recovery

Ischemic stroke triggers excessive oxidative stress and neuroinflammation, which jointly aggravate neuronal injury and limit functional recovery after reperfusion. Although antioxidant therapies have been explored for stroke treatment, single‐component antioxidants often fail to address the complex post‐ischemic microenvironment involving multiple reactive oxygen species (ROS)/ reactive nitrogen species (RNS) species, lipid peroxidation, mitochondrial dysfunction, and inflammatory amplification. Here, we developed a biomimetic antioxidant nanoplatform, PB@PDA‐CA@Mem, by integrating a Prussian blue (PB) nanozyme core, a polydopamine (PDA) interfacial shell, cinnamic acid (CA) loading, red blood cell (RBC) membrane cloaking, and cyclic arginine‐glycine‐aspartic acid peptide (cRGD) modification. The resulting nanoparticles retained representative RBC membrane proteins, exhibited acid‐accelerated CA release under mildly acidic conditions, and showed enhanced brain‐associated accumulation after ischemic injury. PB@PDA‐CA@Mem displayed broad‐spectrum antioxidant activity, with component‐dependent scavenging of ROS/RNS and effective suppression of lipid peroxidation. In HT22 neuronal cells, PB@PDA‐CA@Mem reduced oxidative stress, preserved mitochondrial membrane potential, normalized apoptosis‐related gene expression, and decreased apoptotic cell death under H 2 O 2 or oxygen‐glucose deprivation (OGD) injury. In OGD‐stimulated BV2 microglial cells, PB@PDA‐CA@Mem suppressed pro‐inflammatory gene expression while promoting repair‐associated transcriptional responses. In middle cerebral artery occlusion mice, PB@PDA‐CA@Mem reduced infarct burden, improved neurological and motor functional recovery, attenuated microglia‐associated pro‐inflammatory signaling, and regulated Nrf2/Keap1 antioxidant and nuclear factor kappa B (NF‐κB) /NLRP3‐related inflammatory pathways. ML‐385 partially attenuated these protective effects, indicating that Nrf2‐associated signaling contributed to, but did not exclusively account for, the therapeutic activity of PB@PDA‐CA@Mem. Overall, PB@PDA‐CA@Mem provides an integrated biomimetic therapeutic strategy for ischemic stroke by combining enhanced ischemic brain accumulation, broad‐spectrum oxidative stress regulation, and attenuation of the inflammatory microenvironment.