Stimuli‐Responsive Miktoarm Polymer‐Based Formulations for Fisetin Delivery and Regulatory Effects in Hyperactive Human Microglia

Abstract

Branched star polymers offer exciting opportunities in enhancing the efficacy of nanocarriers in delivering biologically active lipophilic agents. It is demonstrated that the star polymeric architecture can be leveraged to yield soft nanoparticles of vesicular morphology with precisely located stimuli‐sensitive chemical entities. Amphiphilic stars of AB2 (A = PEG, B = PCL) composition with/without oxidative stress or reduction responsive units at the core junction of A and B arms, are constructed using synthetic articulation. Fisetin, a natural flavonoid with remarkable anti‐inflammatory and antioxidant properties, but of limited clinical value due to its poor aqueous solubility, is physically encapsulated into miktoarm star‐derived aqueous polymersomes. Polymersomes and fisetin are evaluated separately, and in combination, in human microglia (HMC3), to show if i) polymersomes are toxic; ii) fisetin reduces the abundance of reactive oxygen species (ROS); and iii) fisetin modulates the activation of ERK1/2. These signaling molecules and pathways are implicated in inflammatory processes and cell survival. Fisetin, both incorporated and nonincorporated into polymersomes, reduces ROS and ERK1/2 phosphorylation in lipopolysaccharide‐treated human microglia, normalizing excessive oxidative stress and ERK‐mediated signaling.

Nanomaterial payload delivery to central nervous system glia for neural protection and repair

“…API payloads range from small molecule drugs to proteins, peptides, and siRNA ( Lee et al, 2021 ; Liu et al, 2021 ; Hernando et al, 2022 ; Zhang M. et al, 2023 ). Most NP API therapies aim to modulate the microglial inflammatory response, polarizing microglia towards the more neuronally protective M2 phenotype to alleviate the inflammatory response and improve functional outcomes ( Papa et al, 2013 , 2016 ; Lu et al, 2014 ; Nance et al, 2015 , 2017 ; Saxena et al, 2015 ; Kim et al, 2017 ; Wang Y. et al, 2018 ; Ellert-Miklaszewska et al, 2019 ; Cahalane et al, 2020 ; Cho et al, 2021 ; Xiao et al, 2021 ; Baghbanbashi et al, 2022 ; Ganbold et al, 2022 ; Guo et al, 2022 ; Hollinger et al, 2022 ; Shin et al, 2022 ; Ishida et al, 2023 ; Kalashnikova et al, 2023 ; Pu et al, 2023 ). NP API delivery to microglia has been shown to improve functional outcomes in many in vivo models of CNS disorders ( Table 1 ), demonstrating that these cells have important implications across CNS pathologies and that modulating their response to injury and disease using NPs has immense potential in improving clinical outcomes.…”

Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia

“…Environmental stressors like chemicals, pollutants, and radiation are known triggers for oxidative stress [44]. Previously, we established that microglia could be activated by lipopolysaccharide (LPS), an element of Gram-negative bacterial cell walls [45]. In this study, we investigated the antioxidant effects of fisetin and quercetin in both microglia and GBM cells when subjected to exogenous stressors, namely L-buthionine sulfoximine (BSO) (Figure S1) or SARS-CoV-2 spike protein (SMT1-1) (Figure 3).…”