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

Cancer therapy is a global biomedical challenge, and a number of promising anticancer therapeutics, such as small-molecule drugs, proteins, nucleic acids, photothermal agents, etc., have been developed or are in development. However, the direct administration of anticancer therapeutics often fails to achieve the desired therapeutic efficacy 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 tissue dysfunction. Polymers offer multiple advantageous properties for the delivery of anticancer therapeutics but are generally poorly targeted to the tumor microenvironment (TME). The relatively lower acidity of the TME compared to normal tissue provides an intrinsic yet highly specific trigger for the development of polymers for the targeted delivery of anticancer therapeutics. Here, we summarize the exquisite strategies for the synthesis of TME acidity-sensitive polymers, elucidate the mechanisms of the polymers’ response to TME acidity, and highlight the applications of the polymers for the delivery of various anticancer therapeutics. Moreover, the potential challenges in translating the polymers into clinical practice are discussed.