Biomimetic Dendrimer–Peptide Conjugates for Early Multi‐Target Therapy of Alzheimer's Disease by Inflammatory Microenvironment Modulation

Abstract

Current therapeutic strategies for Alzheimer's disease (AD) treatments mainly focus on β‐amyloid (Aβ) targeting. However, such therapeutic strategies have limited clinical outcomes due to the chronic and irreversible impairment of the nervous system in the late stage of AD. Recently, inflammatory responses, manifested in oxidative stress and glial cell activation, have been reported as hallmarks in the early stages of AD. Based on the crosstalk between inflammatory response and brain cells, a reactive oxygen species (ROS)‐responsive dendrimer–peptide conjugate (APBP) is devised to target the AD microenvironment and inhibit inflammatory responses at an early stage. With the modification of the targeting peptide, this nanoconjugate can efficiently deliver peptides to the infected regions and restore the antioxidant ability of neurons by activating the nuclear factor (erythroid‐derived 2)‐like 2 signaling pathway. Moreover, this multi‐target strategy exhibits a synergistic function of ROS scavenging, promoting Aβ phagocytosis, and normalizing the glial cell phenotype. As a result, the nanoconjugate can reduce ROS level, decrease Aβ burden, alleviate glial cell activation, and eventually enhance cognitive functions in APPswe/PSEN1dE9 model mice. These results indicate that APBP can be a promising candidate for the multi‐target treatment of AD.

“Drug‐Carrier” Synergy Therapy for Amyloid‐β Clearance and Inhibition of Tau Phosphorylation via Biomimetic Lipid Nanocomposite Assembly

“…The cognitive and memory improvement of mice were examined through MWM test and nesting behavior, respectively. [42] In MWM experiment, AD mice treated with saline showed poorly platform searching performance as expected and obvious deficits in spatial learning with the longest escape latency time (Figure 6B,C), indicating that the coinjection of A𝛽 1-42 and OA in bilateral hippocampus could effectively trigger learning and memory deficit. By contrast, AD mice treated with MB p.o.…”

Photothermal and Photodynamic Therapies via NIR-Activated Nanoagents in Combating Alzheimer’s Disease

“…(3) In addition to Aβ aggregation, other pathological factors in AD pathogenesis can also be targeted or modulated by multipronged agents. These factors include elevated oxidative stress, abnormally hyperphosphorylated tau proteins, irreversible neuron loss, and copper accumulation. − Multifunctional platforms with both therapeutic modalities and modalities that incorporate BBB translocation, stimuli-responsive drug release, multitarget direction, real-time diagnostics, and in situ imaging are indispensable in diminishing the off-target adverse reactions and in the evaluation of therapeutic effects. − Therefore, the inhibition of tau hyperphosphorylation using PDT or PTT will also be a potential therapeutic direction for AD.…”

Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain

“…Intravenous (i.v. ), [30][31][32][33][34][35] intraperitoneal (i.p. ), [36,37] or intraarterial (i.a.)…”

“…[60,61] Other nasal-specific constraints include enzymatic degradation, mucociliary clearance, cavity irritability, and systemic uptake from the lower respiratory mucosa. [35] The risk-benefit evaluation is especially crucial for the IN administration of NPs because of the respiratory system uptake. In addition, to prevent them from getting trapped in the olfactory mucous layer, therapeutic particles should be less than 1000 Daltons MW.…”