Targeted regulation of senescence-associated secretory phenotype with an aptamer-conjugated activatable senomorphic

Background: Senomorphics have been considered as an effective alternative paradigm of senotherapeutics to regulate cellular senescence and related disorders by inhibiting the deleterious effects of senescence-associated secretory phenotype (SASP) components secreted by senescent cells without inducing cell death. However, current senomorphic drugs usually exhibit low selectivity towards senescent cells and inevitably cause unwanted side effects, highlighting the need to develop innovative senomorphic strategies for the specific regulation of cellular senescence. Methods: To address this challenge, here we design a novel class of senomorphics with active cell targeting and activatable activities for selective regulation of SASP by conjugating a senescent cell-targeted aptamer with a SA-β-gal-activated H2S donor. Using senescent BJ cells as a cell model, a series of investigations were performed to evaluate the performance of the engineered senomorphic (Apt-H2SD) for cell-specific regulation of SASP during cellular senescence. Results: Apt-H2SD demonstrated specific binding and accumulation to senescent cells over proliferating cells through the aptamer-mediated cell targeting. Upon internalization, Apt-H2SD was efficiently activated by the accumulated SA-β-gal in senescent cells, leading to the release of H2S precursor and subsequently suppressing the expression of three important SASP factors (IL-6, IL-1β and MMP3) at the mRNA level. Conclusion: Our results strongly support the potential of Apt-H2SD as a valuable senomorphic. With rational design of the molecular structure, this study may provide a general strategy to construct advanced senescencetargeted activatable senomorphics for precise intervention of cellular senescence and age-related diseases.