Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer’s Disease

Inflammatory responses, manifested in excessive oxidative stress and microglia overactivation, together with metal ion-triggered amyloid-beta (Aβ) deposition, are critical hallmarks of Alzheimer's disease (AD). The intricate pathogenesis causes severe impairment of neurons, which, in turn, exacerbates Aβ aggregation and facilitates AD progression. Herein, multifunctional melanin-like metal ion chelators and neuroinflammation regulators (named PDA@K) were constructed for targeted treatment of AD. In this platform, intrinsically bioactive material polydopamine nanoparticles (PDA) with potent metal ion chelating and ROS scavenging effects were decorated with the KLVFF peptide, endowing the system with the capacity of enhanced pathological blood-brain barrier (BBB) crossing and lesion site accumulation via Aβ hitchhiking. In vitro and in vivo experiment revealed that PDA@K had high affinity toward Aβ and were able to hitch a ride on Aβ to achieve increased pathological BBB crossing. The engineered PDA@K effectively mitigated Aβ aggregate and alleviated neuroinflammation. The modulated inflammatory microenvironment by PDA@K promoted microglial polarization toward the M2-like phenotype, which restored their critical functions for neuron care and plaque removal. After 3-week treatment of PDA@K, spatial learning and memory deficit as well as neurologic changes of FAD^4T transgenic mice were largely rescued. Transcriptomics analysis further revealed the therapeutic mechanism of PDA@K. Our study provided an appealing paradigm for directly utilizing intrinsic properties of nanomaterials as therapeutics for AD instead of just using them as nanocarriers, which largely widen the application of nanomaterials in AD therapy.