Intrinsically Bioactive Manganese–Eumelanin Nanocomposites Mediated Antioxidation and Anti‐Neuroinflammation for Targeted Theranostics of Traumatic Brain Injury

Abstract Overproduced reactive oxygen species and the induced oxidative stress and neuroinflammation often result in secondary injury, which is associated with unfavorable prognosis in traumatic brain injury (TBI). Unfortunately, current medications cannot effectively ameliorate the secondary injury at traumatic sites. Here, it is reported that intrinsically bioactive multifunctional nanocomposites (ANG‐MnEMNPs‐Cur, AMEC) mediate antioxidation and anti‐neuroinflammation for targeted TBI theranostics, which are engineered by loading the neuroprotective agent curcumin on angiopep‐2 functionalized and manganese doped eumelanin‐like nanoparticles. After intravenous delivery, efficient AMEC accumulation is observed in lesions of TBI mice models established by controlled cortical impact method, evidenced by T 1 – T 2 magnetic resonance and photoacoustic dual‐modal imaging. Therapeutically, AMEC effectively alleviates neuroinflammation, protects blood–brain barrier integrity, relieves brain edema, reduces brain tissue loss, and improves the cognition of TBI mice. Mechanistically, following the penetration into the traumatic tissues via angiopep‐2 mediated targeting effect, the efficacy of AMEC is synergistically improved by combined functional moieties of curcumin and eumelanin. This is achieved by the alleviation of oxidative stress, inhibition of neuroinflammation via M1‐to‐M2 macrophage reprogramming, and promotion of neuronal regeneration. The as‐developed AMEC with well‐defined mechanisms of action may represent a promising targeted theranostics strategy for TBI and other neuroinflammation‐associated intracranial diseases.