Mitochondria-targeted TPP-MoS₂ with dual enzyme activity provides efficient neuroprotection through M1/M2 microglial polarization in an Alzheimer's disease model

Abstract

Alzheimer's disease (AD) is one of the most common age-associated brain diseases and is induced by the accumulation of amyloid beta (Aβ) and oxidative stress. Many studies have focused on eliminating Aβ by nanoparticle affinity; however, nanoparticles are taken up mainly by microglia rather than neurons, leading poor control of AD. Herein, mitochondria-targeted nanozymes known as (3-carboxypropyl)triphenyl-phosphonium bromide-conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]-functionalized molybdenum disulfide quantum dots (TPP-MoS₂ QDs) were designed. TPP-MoS₂ QDs mitigate Aβ aggregate-mediated neurotoxicity and eliminate Aβ aggregates in AD mice by switching microglia from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype. TPP-MoS₂ QDs cross the blood-brain barrier, escape from lysosomes, target mitochondria and exhibit the comprehensive activity of a bifunctional nanozyme, thus preventing spontaneous neuroinflammation by regulating the proinflammatory substances interleukin-1β, interleukin-6 and tumor necrosis factors as well as the anti-inflammatory substance transforming growth factor-β. In contrast to the low efficacy of eliminating Aβ by nanoparticle affinity, the present study provides a new pathway to mitigate AD pathology through mitochondria-targeted nanozymes and M1/M2 microglial polarization.

Introduction

Alzheimer's disease (AD) is a neuroinflammatory disease [1,2], characterized by the abnormal accumulation of amyloid beta (Aβ) and is a global challenge to human health [3,4]. However, crossing the blood-brain barrier (BBB) and highly specific targeting are challenges that remain for typical drugs or methods [[5], [6], [7]]. Nanoparticles (NPs) exhibit a promising capacity to penetrate the BBB [8,9]. And the modification of NPs can enable receptor-mediated uptake [10,11]. Currently, most studies focus on eliminating Aβ through the affinity of NPs or its ligands to Aβ, but NPs are taken up mainly by microglia, not by neurons [12,13]. Therefore, NPs that target microglia may be an alternative and effective method to clear Aβ and control AD.

Microglia are resident myeloid cells in the central nervous system (CNS) and participate both in normal CNS function and in the response to Aβ accumulation [14,15]. Microglia are categorized into two opposing types: the proinflammatory M1 phenotype and the anti-inflammatory M2 phenotype [[16], [17], [18]]. Endogenous stimuli, including reactive oxide species (ROS), inflammation factors, and aggregated Aβ, persistently activate proinflammatory M1 microglia and finally lead to irreversible neuron loss [15,17,19]. In contrast, the activation of M2 microglia in the AD brain contributes to the clearance of Aβ through the phagocytosis of Aβ [20,21] and to the mitigation of brain inflammation [17] and Aβ toxicity [22]. Therefore, designing novel NPs to switch M1 microglia to M2 microglia would stimulate anti-inflammatory microglia to clear Aβ.

Elevated ROS levels switch M2 microglia to M1 microglia and then induce neurodegenerative diseases and AD [23]. Mitochondria are the main location of ROS production [24]. Protecting mitochondria from oxidative stress and switching microglia into the M2 type would be very useful for the prevention and treatment of AD. Through their metallic character and high d-electron density, the molybdenum-terminated edges of MoS₂ NPs are the main drivers of the catalytic performance of these nanozymes [25]. One of the potential advantages of MoS₂ NPs in the treatment of AD is their beneficial roles in scavenging ROS [26,27]. However, unmodified MoS₂ NPs do not target mitochondria. (3-Carboxypropyl)triphenyl-phosphonium bromide (TPP) is a lipophilic cation that is capable of targeting mitochondria by taking advantage of the negative membrane potential of mitochondria [23,28]. Herein, TPP-conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] functionalized molybdenum disulfide quantum dots (TPP-MoS₂ QDs) were designed to target the mitochondria in microglia. The present study found that TPP-MoS₂ QDs can cross the BBB, target mitochondria, mitigate Aβ-mediated neurotoxicity and eliminate Aβ aggregates in AD mice by acting as nanozymes, inhibiting neuroinflammation and switching M1 microglia to M2 microglia. In contrast to the low efficacy of eliminating Aβ through the affinity of NPs or NP ligands, the present work provides a new pathway to mitigate AD pathology through mitochondria-targeted nanozymes and switching M1/M2 microglial polarization.