Engineering mammalian cells to seek senescence-associated secretory phenotypes

Since the removal of senescent cells in model organisms has been linked to rejuvenation and increased lifespan, senotherapies have emerged to target senescent cells for death. In particular, interleukin-6 (IL6) is a prominent senescence-associated secretory phenotype (SASP) and, thus, seeking IL6 could potentially localize engineered cells to senescent cells for therapeutic intervention. Here, we engineered a chimeric IL6 receptor (IL6Rchi) that generates a Ca²⁺ signal in response to IL6 stimulation. When IL6Rchi was co-expressed with an engineered Ca²⁺-activated RhoA (CaRQ), it enabled directed migration to IL6 in cells that have no such natural ability. Next, the removal of target cells was accomplished by the mechanism of membrane fusion and subsequent death. This work represents a first step towards engineering a cell to target senescent cells that secrete high levels of IL6. For increased specificity to senescent cells, it will likely be necessary for an engineered cell to recognize multiple SASPs simultaneously.