Targeted Delivery of Anticancer Therapeutics with Polymers by Harnessing Tumor Microenvironment Acidity

Cancer therapy is a global biomedical challenge, anda number ofpromising anticancer therapeutics, such as small-molecule drugs, proteins,nucleic acids, photothermal agents, etc., have beendeveloped or are in development. However, the direct administrationof anticancer therapeutics often fails to achieve the desired therapeuticefficacy due to their low bioavailability and poor tissue selectivity,leading to relapse or severe side effects such as immunosuppression,chronic inflammatory responses, mutagenesis, and long-term tissuedysfunction. Polymers offer multiple advantageous properties for thedelivery of anticancer therapeutics but are generally poorly targetedto the tumor microenvironment (TME). The relatively lower acidityof the TME compared to normal tissue provides an intrinsic yet highlyspecific trigger for the development of polymers for the targeteddelivery of anticancer therapeutics. Here, we summarize the exquisitestrategies for the synthesis of TME acidity-sensitive polymers, elucidatethe mechanisms of the polymers' response to TME acidity, andhighlight the applications of the polymers for the delivery of variousanticancer therapeutics. Moreover, the potential challenges in translatingthe polymers into clinical practice are discussed.