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

Abstract

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.

Recent advances in nanotechnology for combating Alzheimer's disease

“…Recently, we have proposed a multifunctional melanin-like NP with the abilities of pathological BBB crossing, metal-ion chelation and neuroinflammation regulation against AD. 34 This nanoplatform (named PDA@K) was constructed by intrinsically bioactive material polydopamine NPs (PDA) with potent metal-ion chelating and ROS scavenging effects. The KLVFF peptide was decorated on the surface of PDA@K for pathological BBB crossing and lesion site accumulation via Aβ hitchhiking.…”

“…78 A series of reversible noncovalent or covalent inhibitors have been proposed to inhibit Ab aggregation and toxicity. 34,[79][80][81][82] A review from Du and co-workers summarized the current strategies for modulating Ab aggregation with multifunctional agents, such as aggregation inhibitors, copper chelators, Ab photoxidation, and dissociation of Ab aggregates. 14 Here, we mainly focus on recent advances in nanotechnology for Ab and tau protein targeting.…”

“…Recently, we have proposed a multifunctional melanin-like NP with the abilities of pathological BBB crossing, metal-ion chelation and neuroinflammation regulation against AD. 34 This nanoplatform Fig. 1 Tau-targeted nanochaperone for selectively capturing intracellular pathological tau and inhibiting their aggregation in neurons.…”

“…33 Recently, some studies have focused on the heterogeneous microenvironment of lesions of the BBB for specific targeting strategies. 34 However, intracellular transport with brain endothelial cells is generally ignored after recognizing the receptors on the BBB, which may lead to a low BBB penetration efficiency. Furthermore, the following steps, from diseased cell targeting and internalization to finally controlled-drug release, should also be reasonably designed to achieve ideal therapeutic effects and reduce side effects.…”

Natural Polyphenolic Nanodots for Alzheimer's Disease Treatment

“…In turn, inflammatory microenvironment causes more Aβ accumulation and microglia dysfunction, which strictly promotes AD progression. [ 5 ] Also, tau protein is hyperphosphorylated and accumulated to form neurofibrillary tangles with toxicity, causing severe neuron and synaptic loss. [ 6 ] Aimed at lowering the level of Aβ plaque deposition, several potential therapeutics have been proceeded and the Aβ‐targeted monoclonal antibody (aducanumab) has been approved fast by the U.S. Food and Drug Administration (FDA), however, which has been controversial due to its unclear therapeutic effects that the negative trial results were not related with amyloid hypothesis directly and necessarily.…”