A brain-targeted biomimetic iron-porphyrin covalent organic framework nanoplatform for Alzheimer's disease: synergistic intervention via antioxidant, Aβ-regulating and immunomodulatory effects.

The pathological progression of Alzheimer's disease (AD) involves multiple interconnected pathways, including β-amyloid (Aβ) deposition, oxidative stress, and microglial dysfunction, which together form a self-reinforcing vicious cycle. This complexity poses a major challenge to conventional single-target therapeutic strategies. To address this limitation, we developed a biomimetic nanoplatform integrating active brain targeting, multiple therapeutic bioactivities, and immunomodulatory function. The core of this platform was an iron-porphyrin-based covalent organic framework (COF) that possesses enzyme-mimetic antioxidant activity, metal-ion-chelating capability, and Aβ-modulating properties. The COF core was cloaked with a BV2 microglial membrane (BM) to enhance biocompatibility and further functionalized with Angiopep-2 peptide to enable efficient blood brain barrier (BBB) penetration. In vitro studies demonstrated that the platform effectively scavenged various reactive oxygen species, achieved a copper-ion chelation rate of 41.78%, inhibited Aβ aggregation, and depolymerized pre-formed fibrils. At the cellular level, the nanoplatform not only protected neurons from β-amyloid-induced toxicity but also improved the redox status and mitochondrial function of microglia. Furthermore, it promoted the polarization of microglia from the pro-inflammatory M1 phenotype toward the neuroprotective M2 phenotype, which was correlated with enhanced β-amyloid phagocytic capacity. In APP/PS1 (APPswe/PSEN1dE9) transgenic mice, treatment with this nanoplatform markedly reduced cerebral Aβ plaque deposition, attenuated neuroinflammation and oxidative stress, and improved BBB integrity, ultimately leading to the remarkable recovery of spatial learning, memory, and spontaneous exploration abilities in mice. In summary, this integrated nano-strategy, which combines delivery, clearance, and modulation, represents an effective multi-target approach for intervening in the complex pathological network of AD.