Rational Protein Molecular Design of Hydrophobic Interior-Modified Ferritin Enables Efficient Lycopene Delivery for Ameliorating Aging-Related Cognitive Impairment.

Lycopene shows potential against aging-related cognitive decline but suffers from poor stability, low blood-brain barrier penetration, and inefficient delivery. Native rHuHF is biocompatible yet achieves only ∼6% lycopene encapsulation due to its hydrophilic cavity. Here, a recombinant mutant human heavy-chain ferritin (rXHF) with a hydrophobic interior was engineered by replacing four polar residues with tryptophan. rXHF maintains the 24-mer nanocage structure and exhibits enhanced hydrophobicity. It achieves 74.9 ± 2.5% encapsulation efficiency and 17.8 ± 0.6% loading efficiency (2.9-fold that of rHuHF). At a molar ratio of 1:200, the DPPH scavenging rate reached 30.06 ± 9.2%. In D-galactose-induced aging mice, rXHF-LYC dose-dependently improved spatial learning/memory, reduced hippocampal senescence, and modulated oxidative stress, neuroinflammation, and synaptic plasticity via BDNF/TrkB. PC12 assays confirmed endocytic uptake, ROS scavenging, apoptosis inhibition, and preserved acetylcholine synthesis. Thus, hydrophobic ferritin modification enables brain-targeted lycopene delivery, offering a novel strategy for age-related neurodegenerative diseases.