An orally administrable hydrogen-bonded organic framework (HOF)-based nanoreactor to reprogram metabolism for senescence intervention

ABSTRACT Aging poses significant health challenges due to functional decline and increased disease susceptibility. Modulating age-related metabolic dysregulation offers a promising therapeutic avenue. However, the efficacy of oral therapies is severely hampered by the degradation of active agents in the harsh gastrointestinal (GI) tract. Here, we report an orally administrable hydrogen-bonded organic framework (HOF)-based nanoreactor (MAO@NADH@PB@O-HOF@PEG) designed to intervene in senescence by modulating metabolic pathways. The HOF scaffold exhibits exceptional stability in ultra-acidic conditions and boiling water, providing a robust shield for its encapsulated delicate cargo against GI degradation. This protection enables prolonged in situ catalysis within the intestine, leading to reprogramming of the gut metabolism by a catalytic degradation of the aging-elevated metabolite isoamylamine (IAA) in the intestine, serum and cerebrospinal fluid (CSF). The apoptosis and inflammation driven by elevated IAA levels are mitigated through the catalytic degradation of IAA by the HOF-based anti-aging nanoreactor. Oral administration of MAO@NADH@PB@O-HOF@PEG to aged mice significantly alleviated cognitive decline, neuronal damage and neuroinflammation. This study highlights the potential of robust HOF materials in the development of advanced oral delivery systems and geroprotective therapeutics.