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 AB 2 (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.