Nanoenabled Sequestration of Redox Copper Modulates Lysozyme Aggregation and Maintains Lipid Homeostasis to Alleviate Mitochondrial Health

Abstract Abnormal amyloid deposition is a prominent hallmark of several neurodegenerative diseases (NDs), however, therapies involving direct amyloid degradation have resulted limited success, underscoring the need for refined intervention strategies and alternative therapeutic targets. Emerging evidence implicates dysregulated lipid metabolism, particularly aberrant lipid droplet (LD) accumulation, as a key contributor to ND pathology. Notably, intracellular lipid homeostasis is tightly regulated by copper (Cu) levels, and elevated Cu concentrations have also been detected in amyloid aggregates in ND brains, suggesting mechanistic link between metal dyshomeostasis, amyloid aggregation, and lipid dysregulation. To address this, we developed chemically modified plant‐based fluorescent carbon dots (PEI@HCD PEG , ∼12 nm) with specific Cu‐chelating ability. PEI@HCD PEG effectively mitigated Cu‐induced protein aggregation (∼2.8 fold reduction) and significantly decreased intracellular LD accumulation (∼1.25 fold) by inhibiting lipid peroxidation and modulating lipid metabolic pathways. Lipidomic analysis revealed that PEI@HCD PEG pretreatment led to reduced levels of neutral lipids, including cholesteryl esters (∼1.5 fold) and triglycerides (∼1.2 fold). Furthermore, PEI@HCD PEG decreased LD diameter from ∼7µm to ∼3µm, indicating restored lipid homeostasis. Consistent results were also observed in C. elegans studies. These multi‐dentate, metal ion chelator nanoparticles hold promise as novel therapeutic agents for NDs.