Facile Engineering of Biocompatible Materials with pH‐Modulated Degradability

O N Biodegradable polymeric biomaterials, including polyesters, polyanhydrides, and polyorthoesters have played important roles in biomedical fi elds such as tissue engineering, drug delivery, gene therapy, and vaccination. [ 1 ] These materials defi nitely contribute to the big success in developing new medical treatments, especially in controlled drug-delivery systems. [ 2–4 ] Nevertheless, critical problems in biocompatibility, stimuli-sensitivity, degradation, and numerous other areas remain. [ 5 , 6 ] For example, polymers with acidic byproducts postdegradation may lead to signifi cant local infl ammation. Such a response limits the use of these materials in some cases, such as myocardial infarction therapy, since undesired infl ammatory responses in the myocardium can result in tissue fi brosis and cardiac dysfunction. [ 7 ] These proinfl ammatory materials encounter the same dilemma in the case of protein delivery and gene therapy, in which denaturation and incomplete release or even degradation of laden biomacromolecules may occur as a result of low pH caused by the acidic metabolites. [ 8 , 9 ] On the other hand, targeting diseased sites, specifi c tissues, and subcellular organelles or delivery through specifi c intracellular pathways are necessary for some biotherapeutics (proteins and nucleic acids for instance) to effi ciently perform their pharmacological activities. [ 10 , 11 ] Materials that can undergo rapid, pH-sensitive degradation or hydrolysis are of interest for these purposes, [ 12–16 ] given the lower pH values in tumor tissue (pH < 6.5), infectious and infl ammatory sites (pH ∼ 6.5) as well as in lysosomal compartments (pH 4 ∼ 5). [ 17 , 18 ] To this end, there is an urgent demand for developing alternative materials that overcome the drawbacks of biodegradable acid-producing polymers, while possessing the desirable sensitivity. Whereas synthetic polymers offer a wealth of opportunities to materials