Stimuli‐Responsive Aptamer‐Drug Conjugates for Targeted Drug Delivery and Controlled Drug Release

Abstract Chemotherapy is widely used for cancer therapy but with unsatisfied efficacy, mainly due to the inefficient delivery of anticancer agents. Among the critical “five steps” drug delivery process, internalization into tumor cells and intracellular drug release are two important steps for the overall therapeutic efficiency. Strategy based on active targeting or TME‐responsive is developed individually to improve therapeutic efficiency, but with limited improvement. However, the combination of these two strategies could potentially augment the drug delivery efficiency and therapeutic efficiency, consequently. Therefore, this work constructs a library of stimuli‐responsive aptamer‐drug conjugates (srApDCs), as “dual‐targeted” strategy for cancer treatment that enables targeted drug delivery and controlled drug release. Specifically, this work uses different stimuli‐responsive linkers to conjugate a tumor‐targeting aptamer (i.e., AS1411) with drugs, forming the library of srApDCs for targeted cancer treatment. This design hypothesis is validated by the experimental data, which indicated that the aptamer could selectively enhance uptake of the srApDCs and the linkers could be cleaved by pathological cues in the TME to release the drug payload, leading to a significant enhancement of therapeutic efficacy. These results underscore the potential of the approach, providing a promising methodology for cancer therapy.