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

Manik Bathla,Trilok Chand Saini,Nandini Teji,Shiwani Randhawa,Rahul Bhardwaj,Amitabha Acharya

Published 2025 in Small

ABSTRACT

Abnormalamyloid deposition is a prominent hallmark of several neurodegenerative diseases (NDs), however, therapies involving direct amyloid degradation haveresulted 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, intracellularlipid homeostasis is tightly regulated by copper (Cu) levels, and elevated Cuconcentrations 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 modifiedplant‐based fluorescent carbon dots (PEI@HCDPEG, ∼12 nm) withspecific Cu‐chelating ability. PEI@HCDPEG effectively mitigatedCu‐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@HCDPEG pretreatment led to reduced levels ofneutral lipids, including cholesteryl esters (∼1.5 fold) and triglycerides(∼1.2 fold). Furthermore, PEI@HCDPEG decreased LD diameter from ∼7µmto ∼3µm, indicating restored lipid homeostasis. Consistent results were also observedin C. elegans studies. These multi‐dentate, metal ion chelator nanoparticles hold promise as novel therapeutic agents for NDs.

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