Adaptive Peroxynitrite Scavenging–Driven Synergistic Drug Release for Targeted and Efficient Theranostics in Ischemic Stroke

ABSTRACT Ischemic stroke (IS), with its high disability and mortality rates, remains a critical global health challenge, while current theranostic strategies fail to meet the demands of early diagnosis and timely intervention. Here, we report a breakthrough small‐molecule theranostic system ( ESL ) that integrates celastrol (Cel), a selective peroxynitrite (ONOO − )‐responsive trigger, and a hemicyanine‐based near‐infrared fluorophore. ESL undergoes a distinctive 1,4‐elimination reaction upon ONOO − activation, producing a 33‐fold fluorescence enhancement at 762 nm and enabling rapid visualization of ischemic lesions within 10 min. Therapeutically, ESL implements a dual‐mode strategy of instant scavenging and targeted delivery, simultaneously eliminating ONOO − ‐induced oxidative stress and releasing Cel to suppress neuroinflammation. This precise delivery markedly reduces systemic toxicity, achieving a superior safety profile compared with free Cel. Mechanistic studies further reveal that ESL inhibits the IL‐17/NF‐κB pathway, modulates microglial polarization, and suppresses pro‐inflammatory cytokines. Collectively, this work establishes an integrated “diagnosis–treatment–monitoring” paradigm for IS and provides a versatile platform for precision therapy of central nervous system disorders.