Programmable artificial chaperone for aging intervention

Aging is marked by a decline in cellular proteostasis, leading to protein misfolding, oxidative modifications, and aggregation, thereby impairing cellular function and accelerating senescence-related deterioration. Strengthening proteostasis networks can mitigate these disruptions and restore cellular homeostasis. Here, a programmable DNA building blocks-based artificial chaperone, Th^Ribo, was constructed to selectively target ribosomes and employ a reductive repair cascade that prevents misfolding and aggregation caused by oxidative post-translational modifications (oxidative PTMs) of newly synthesized proteins, repairs already damaged residues, and restores proteostasis balance. In aging mice, Th^Ribo effectively suppressed senescence-associated signaling pathways, including the canonical tumor protein p53 (p53)/p21/p16 axis and the stress-responsive c-Jun N-terminal kinase (JNK) pathway, improved brain protein homeostasis, reduced oxidative stress markers, enhanced motor performance, and exhibited desirable biocompatibility. This ribosome-targeted, programmable artificial chaperone provides a versatile platform for maintaining proteostasis and is expected to offer a promising strategy for anti-aging interventions.