image: (a) The construction process of the MAO@NADH@PB@O-HOF@PEG nanoreactor, illustrating the encapsulation of MAO, NADH, and PB within the HOF, followed by PEGylation. (b) The in vivo therapeutic mechanism showing the nanoreactor surviving the gastrointestinal tract to reduce reactive oxygen species (ROS) and deplete the aging-related metabolite isoamylamine (IAA) in the gut. (c) The overall therapeutic outcomes demonstrating that the nanoreactor prevents IAA circulation to the central nervous system, thereby rescuing cognitive decline, microglial apoptosis, and neuronal damage associated with aging.
Credit: ©Science China Press
Aging brings a host of health challenges, primarily due to functional decline and an increased susceptibility to various diseases. While modulating age-related metabolic changes offers a potential therapeutic route, creating effective oral treatments has been hampered because the acidic environment and enzymes of the gastrointestinal (GI) tract typically degrade active biologic agents before they can take effect.
Recently, a team of researchers led by Professor Xiaogang Qu from the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, has reported a novel method to address this issue. They developed an orally administrable "nanoreactor" based on a hydrogen-bonded organic framework (HOF) designed to intervene in the aging process by modulating gut metabolism.
The key to this platform, designated as MAO@NADH@PB@O-HOF@PEG, is its high structural stability. The HOF scaffold can endure acidic conditions and high temperatures, acting as a protective shield for its encapsulated cargo against GI degradation. Inside this framework, the researchers encapsulated an integrated combination of active components: monoamine oxidase (MAO) to degrade specific metabolites, Prussian blue (PB) nanoparticles to act as multi-enzyme-mimicking antioxidants, and nicotinamide adenine dinucleotide (NADH). To enhance its retention, the nanoreactor is coated with polyethylene glycol (PEG), a standard polymer that helps the complex adhere to the intestine for localized action.
The therapy targets isoamylamine (IAA), a gut-derived metabolite that increases as mammals age and is associated with age-related cognitive decline, microglial cell apoptosis, and neuroinflammation. Once administered, the nanoreactor reaches the gut, where the encapsulated MAO catalyzes the degradation of IAA. Concurrently, the Prussian blue nanoparticles work to scavenge reactive oxygen species (ROS), mitigating the oxidative stress that can compromise the gut barrier during aging.
When the researchers orally administered this nanoreactor to aged mice, the therapeutic results were encouraging. The treatment reduced the elevated levels of IAA in the intestine, as well as systemically in the serum and cerebrospinal fluid. Behaviorally, the treated aged mice showed measurable improvements in spatial learning and recognition memory during tests like the Morris water maze. Furthermore, histological analysis indicated that the therapy mitigated neuronal damage, cellular apoptosis, and neuroinflammation in the tested models.
Beyond its application for studying senescence, this research points to broader potential applications for drug delivery. The stability and metal-free nature of the HOF platform make it a promising candidate for delivering other vulnerable biologic drugs—such as therapeutic peptides—orally, shielding them from digestive enzymes without the safety risks associated with metal ion accumulation found in some other framework materials.
By transforming the gut environment into a site for localized biocatalysis, this engineered nanoreactor provides new possibilities for modulating the gut metabolome and exploring treatments for age-associated conditions through oral catalytic therapies.