Strategic chemical synthesis and application of nanocarriers responsive to the tumor microenvironment

In contrast to normal tissues and cells, the tumor microenvironment (TME) exhibits distinct physiological attributes, including elevated concentrations of reactive oxygen species and heightened levels of glutathione, as well as lower pH and pronounced hypoxia and abnormal expression of enzymes. Leveraging these distinctive characteristics, a diverse array of responsive nanocarriers can be meticulously engineered. Currently, drug delivery methods employing nanocarriers predominantly fall into three categories: physical encapsulation, intermolecular forces, and chemical bonding, each offering unique advantages. Notably, nanocarriers prepared by chemical synthesis methods enables superior control over drug distribution and release, imparting greater stability and enhanced targeting capabilities to the nanodrug system within the in vivo tumor tissue environment. Herein, this review aims to consolidate the latest advancements in the fields of TME-responsive nanocarriers, categorizing them based on the types of responsiveness, with particular emphasis on chemical bond synthesis, such as (1) pH-responsive chemical bonds: acetal/ketal, imine/hydrazone, anhydride and esters; (2) redox-responsive chemical bonds: disulfide/ diselenium bonds, thioketone bonds and phenylborate bonds; (3) hypoxia-responsive chemical bonds: azo bonds, nitro bonds, quinone. Finally, associated challenges and outline future prospects are discussed. We hoped that this review will serve as a guiding beacon for researchers, propelling the advancement of TME-responsive nanocarriers. In this review, we provided a detailed summary of the types and characteristics of responsive chemical bonds in the tumor microenvironment, such as pH responsive, oxidative responsive, reduction responsive, hypoxia responsive, enzyme responsive etc., and the applications of various nanocarriers in drug delivery, phototherapy, immunotherapy, and radiation therapy were discussed • The strategic chemical synthesis of responsive chemical bonds in the tumor microenvironment are summarized. • Some innovative concepts and design strategies of nanocarriers in the tumor microenvironment are introduced. • Applications of various nanocarriers in the tumor microenvironment are reviewed. • Challenges and outlook of responsive chemical bonds in the tumor microenvironment are discussed.