Advances in artificial metabzymes for molecular metabolism restoration in aging-related diseases.

Aging-related diseases impose an escalating burden on global healthcare, with their pathogenesis closely linked to dysregulation of molecular metabolism, characterized by the accumulation of harmful metabolites, including reactive oxygen species and glucose, alongside the depletion of essential metabolites such as nicotinamide adenine dinucleotide and glutathione. Over the past decade, artificial metabzymes-particularly nanozymes engineered to catalyze metabolic reactions-have emerged as promising candidates for restoring molecular metabolic homeostasis, offering potential therapeutic avenues for aging-related diseases. Realizing their full potential, however, requires a systematic understanding of aging-associated metabolic abnormalities as well as the chemical design and structure-activity relationships of these materials, which collectively underpin effective molecular metabolism restoration. This review summarizes the chemical design and biomedical applications of nano-engineered artificial metabzymes aimed at restoring molecular metabolism in aging-related diseases. We begin by outlining the key metabolic alterations underpinning these diseases, establishing a rationale for the design of artificial metabzymes. Next, we focus on the chemical designs and catalytic mechanisms of artificial metabzymes, emphasizing their ability to rectify these metabolic imbalances. Furthermore, we summarize recent advances in their applications across a spectrum of aging-related diseases, spanning neurodegenerative, musculoskeletal, cardiovascular, and metabolic diseases. Finally, current challenges and forward-looking perspectives of artificial metabzymes are discussed, aiming to steer future innovations in the development of next-generation artificial metabzymes.