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Due to the poor stability and adverse effects of chemotherapy drugs, such as gemcitabine, the current effectiveness of traditional chemotherapy is minimal. Some patients also show a low response rate to immunotherapy. Therefore, a novel material PD‐L1‐GEMs is designed and synthesized with targeted specificity. PD‐L1‐GEMs specifically bind to bladder cancer cells. Free gemcitabine cleaved by a phosphatase enters bladder cancer cells through the macropinocytosis pathway and induces cytotoxicity. PD‐L1‐GEMs show good stability, binding specificity, and significant inhibitory effects in vitro. Two bladder tumor models (subcutaneous model and in situ model) show inhibition of growth and progression in PD‐L1‐GEMs treatment, as well as good biosafety in vivo. The PD‐L1 aptamer blocks the binding of PD‐L1 on the tumor cell surface to PD‐1 on T lymphocytes, restoring their immune function, inducing cytokine production and aggregation, and exerting an immune killing role on bladder cancer cells. PD‐L1‐GEMs represent a successful chemotherapy–immunotherapy strategy for bladder cancer. [ABSTRACT FROM AUTHOR]

• The first report of the use of a CD71 and CD44 aptamer as a drug carrier to target and eliminate both CSCs and non-CSCs. • The first report of the use of dual-aptamer based drug delivery system to treat bladder cancer. • CD71-CD44-GEMs exerted obvious anticancer effect in three types of tumor xenograft mice models. • CD71-CD44-GEMs showed excellent biosafety in three types of tumor xenograft mice models. Conventional chemotherapy lacks the ability to specifically target cancer cells, thus although it eliminates tumor tissues to some extent, it also damages normal tissues and organs. Meanwhile, cancer stem cells (CSCs)-induced tumor regrowth and drug resistance limits the application of some chemotherapy drugs. In this study, the CD71/CD44 dual-aptamer-gemcitabine (CD71-CD44-GEMs) conjugate was designed to treat bladder cancer through the co-targeting by CD71 of bladder cancer cells and by CD44 of bladder CSCs. A series of studies were used to evaluate the binding specificity and the in vitro and in vivo anti-cancer effects. We observed that CD71-CD44-GEMs selectively bound to and exerted a high inhibitory effect on bladder cancer in vitro and in vivo. Besides, CD71-CD44-GEMs can inhibit the formation of the tumorsphere and demonstrated a higher binding affinity and inhibitory efficacy than CD71-GEMs or CD44-GEMs (GEM delivered by a single target aptamer) in bladder cancer. Hence, CD71-CD44-GEMs represents a promising approach to treating bladder cancer for its high efficacy in drug delivery and ability to eliminate both bladder cancer cells and CSCs. [ABSTRACT FROM AUTHOR]