Click chemistry-based drug delivery systems for targeted cancer therapy

Drug delivery systems (DDSs) play a crucial role in improving the efficacy and reducing the side effects of cancer treatment. However, traditional DDSs face challenges such as poor targeting, tissue penetration, and uncontrolled drug release. Click chemistry offers a powerful tool for addressing these limitations by enabling precise modification and targeting of DDSs. This review explores the application of click chemistry in the construction of active targeted DDSs for cancer therapy, focusing on two key strategies: in vitro and in vivo. In vitro strategies involve direct coupling of targeting agents to carrier materials, while in vivo strategies utilize metabolic engineering and click chemistry for cell labeling and drug delivery. The review discusses the advantages and limitations of different click chemistry reactions, including copper-catalyzed azide-alkyne cycloaddition (CuAAC), strain-promoted azide-alkyne cycloaddition (SPAAC), inverse electron-demand Diels-Alder (IEDDA) reaction, thiol-ene reaction, sulfur (VI) fluoride exchange (SuFEx) reaction, and selenium-nitrogen exchange (SeNEx) reaction. It also highlights recent advancements in using click chemistry to construct multifunctional DDSs, such as tumor-targeted biomimetic systems and cell-based delivery systems. Finally, the review outlines the challenges and future directions of click chemistry in drug delivery, emphasizing the need for precise control, expanded toolkits, and integration with emerging technologies to create intelligent, multifunctional DDSs with enhanced therapeutic efficacy and reduced side effects.