Inflammatory processes are activated following ischemic stroke that lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation‐induced secondary injury. Here, we report that SynB1‐ELP‐p50i, a novel protein inhibitor of the nuclear factor kappa B (NF‐κB) inflammatory cascade bound to the drug carrier elastin‐like polypeptide (ELP), decreases NF‐κB induced inflammatory cytokine production in cultured macrophages, crosses the plasma membrane and accumulates in the cytoplasm of both neurons and microglia in vitro, and accumulates at the infarct site where the blood–brain barrier (BBB) is compromised following middle cerebral artery occlusion (MCAO) in rats. Additionally, SynB1‐ELP‐p50i treatment reduces infarct volume by 11.86% compared to saline‐treated controls 24 h following MCAO. Longitudinally, SynB1‐ELP‐p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP‐delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.

Inflammatory processes are activated following ischemic strokes and lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to drug carrier elastin-like polypeptide (ELP), is able to enter both neurons and microglia, cross the blood-brain barrier, localize exclusively in the ischemic core and penumbra in Wistar-Kyoto and spontaneously hypertensive rats (SHRs), and reduce infarct volume in male SHRs. Additionally, in male SHRs, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP-delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.