pH-Responsive Amphiphilic Carboxylate Polymers: Design and Potential for Endosomal Escape

The intracellular delivery of emerging biomacromolecular therapeutics, such as genes, peptides, and proteins, remains a great challenge. Unlike small hydrophobic drugs, these biotherapeutics are impermeable to the cell membrane, thus relying on the endocytic pathways for cell entry. After endocytosis, they are entrapped in the endosomes and finally degraded in lysosomes. To overcome these barriers, many carriers have been developed to facilitate the endosomal escape of these biomacromolecules. This mini-review focuses on the development of anionic pH-responsive amphiphilic carboxylate polymers for endosomal escape applications, including the design and synthesis of these polymers, the mechanistic insights of their endosomal escape capability, the challenges in the field, and future opportunities.