pH-Responsive Materials Exploit Acidic Tumor Microenvironments for Precision Biomedical Imaging and Targeted Therapy

The tumor microenvironment (TME) is often characterized by its acidic pH, a distinct pathological hallmark that can be leveraged for highly specific therapeutic and diagnostic interventions. Current standard-of-care approaches for cancer often lack the necessary precision, leading to off-target effects and suboptimal drug concentrations at the disease site. Exploiting the TME's acidity offers a promising strategy to achieve spatial and temporal control over drug delivery and imaging contrast, thereby enhancing diagnostic accuracy and therapeutic specificity.

This systematic review outlines the design principles and diverse applications of pH-responsive materials in both biomedical imaging and therapy. Researchers detailed the fundamental chemical mechanisms enabling pH responsiveness, including dynamic covalent bonds (e.g., acylhydrazone, imine, orthoester, borate ester), metal-ligand coordination bonds, and pH-dependent noncovalent interactions. These principles were then applied to various nanocarrier platforms, such as polymeric micelles, liposomes, hydrogels, metal-organic frameworks (MOFs), PROTAC conjugates, and self-assembling peptides, all engineered to undergo structural or functional changes specifically under acidic conditions.

The review found that pH-responsive materials enable transformative applications by converging smart material design with advanced imaging modalities. Key findings include the development of activatable probes, which provide high-contrast functional imaging by responding to acidic TME conditions. These materials facilitate multistimuli responsive theranostics, combining diagnostic capabilities with therapeutic delivery. Furthermore, they allow for organelle-precision targeting, ensuring drugs reach specific intracellular compartments, and spatiotemporally programmed release systems for controlled drug kinetics. The underlying mechanisms, such as dynamic covalent bond formation and breakage, allow for precise control over material morphology and drug payload release. This targeted approach significantly enhances both diagnostic accuracy and therapeutic specificity, offering the potential for real-time treatment monitoring. For instance, self-assembling peptides can transition from soluble states to nanostructures, trapping drugs and releasing them only in the acidic TME, leading to enhanced therapeutic indices.