Cellular senescence disrupts tissue homeostasis and diminishes physiological integrity, leading to the accumulation of senescent cells (SCs) in multiple senescence-associated diseases such as chronic kidney disease (CKD). Treatment of SCs has been approved to be a feasible approach to these diseases. However, curing SCs in different cell types remains challenging. In this study, we leveraged the high expression of glutaminase (GLS) in SCs to develop a drug delivery system utilizing γ-poly glutamic acid (γ-PGA) conjugated with octadecylamine (ODA) to encapsulate rapamycin (RP), resulting in a GLS-responsive drug delivery system, designated as RPPO. In a model of drug induced senescence, the γ-PGA component of RPPO was degraded by cellular GLS, facilitating the release of encapsulated RP and rejuvenating SCs by restoring the autophagic capacity. Additionally, in a model of CKD in mice, RPPO enhanced recovery by rejuvenating SCs, reducing fibrosis, and alleviating inflammation. Thus, this senescent cell-responsive drug delivery system presents a novel approach for the treatment of CKD.