posted on 2024-03-06, 14:37authored byYining Liu, Dongju Zhao, Fan Yang, Caihua Ye, Ziyao Chen, Yihan Chen, Xiaomeng Yu, Jiyao Xie, Yan Dou, Jin Chang
Ferroptosis is a vital driver of
pathophysiological consequences
of Alzheimer’s disease (AD). High-efficiency pharmacological
inhibition of ferroptosis requires comprehensive coordination of diverse
abnormal intracellular events, which is an urgent problem and great
challenge for its application in AD treatment. Herein, a triphenylphosphonium-modified
quercetin-derived smart nanomedicine (TQCN) is developed for multipronged
anti-ferroptosis therapy in AD. Taking advantage of the favorable
brain-targeting and mitochondria-locating properties, TQCN can efficiently
chelate iron through phytopolyphenol-mediated spontaneous coordination
and self-assemble into metal-phenolic nanocomplexes in situ, exerting escalating exogenous offensive effects to attenuate iron
overload and its induced free radical burst. Meanwhile, the Nrf2 signaling-mediated
endogenous defensive system is reconstituted to restore iron metabolism
homeostasis represented by iron export and storage and enhance cytoprotective
antioxidant cascades represented by lipid peroxidation detoxification.
Benefiting from the multifaceted regulation of pathogenic processes
triggering ferroptosis, TQCN treatment can ameliorate various neurodegenerative
manifestations associated with brain iron deposition and rescue severe
cognitive decline in AD mice. This work displays great promise of in situ self-assembled phytopolyphenol-coordinated intelligent
nanotherapeutics as advanced candidates against ferroptosis-driven
AD progression.