Redox homeostasis is crucial for cellular function, and its disruption is associated with numerous diseases and age-related pathologies. Superoxide (·O₂⁻), a key reactive oxygen species (ROS), functions as a crucial signaling molecule under normal physiological processes; however, both its excessive accumulation and deficiency can lead to significant detrimental effects on organismal health. Inspired by the natural enzyme superoxide dismutase (SOD), which alleviates oxidative stress by neutralizing excess free radicals and modulates intracellular ROS levels to activate anti-aging pathways, we bioengineered a novel "superoxide buffering formulation" (SOD Buffer) to precisely regulate mitochondrial superoxide levels. Using C. elegans as a model, we show that SOD Buffer reduces superoxide accumulation under oxidative stress (e.g., UV exposure) and restores superoxide levels under its depletion (e.g., post-MitoQ treatment), without affecting general ROS level. Mechanistically, SOD Buffer modulates superoxide levels to activate the mitochondrial unfolded protein response (UPR^mt), evidenced by the increased HSP-6 expression. This activation is mediated by the transcription regulators ATFS-1 and DVE-1, which govern mitochondrial stress responses. Functionally, SOD Buffer extends average lifespan by 36.98% and improves aging-related behaviors in C. elegans in a UPR^mt dependent manner. These findings highlight the therapeutic promise of targeted superoxide modulation to maintain mitochondrial health and promote longevity.

It is well reported that cellular ferritin reduces the intracellular oxidative stress by sequestering excess ferrous ions, preventing them from participating in Fenton reactions that generate damaging harmful reactive oxygen species (ROS). Here we show a novel property of the native human ferritin H subunit nanoparticles (HFn NPs), which can function as catalase by effectively decomposing H₂O₂ into H₂O and O₂ in vivo that plays an important role in maintaining cellular redox homeostasis and in disease resistance. It was revealed that the catalase-like activity of HFn can be greatly increased by loading iron ions within the cavity of HFn nanocage. Moreover, HFn and iron-loaded HFn (HFn-Fe) can largely eliminate the oxidative damage caused by excess H₂O₂ to live cells or Caenorhabditis elegans (C. elegans). Feeding HFn or HFn-Fe to C. elegans A30P Parkinson’s disease (PD) model significantly ameliorated the α-synuclein toxicity and alleviated the dendrite dysfunction in C. elegans PD models by substantively scavenging the in vivo H₂O₂. This work demonstrates that the revealed novel catalase-like property of native HFn and HFn-Fe NPs may play an important role in maintaining cellular redox homeostasis and can be used as an effective therapeutic strategy against neurodegenerative diseases caused by redox dysregulation.