pH-Responsive Materials for Therapy and Precision Biomedical Imaging

The acidic tumor microenvironment (TME) presents a key pathological hallmark that can be exploited for targeted therapeutic and diagnostic interventions. This review systematically outlines the design and application of pH-responsive materials in biomedical imaging and therapy, emphasizing their role in achieving spatial and temporal control over drug delivery and imaging contrast. We first detail the fundamental chemical mechanisms underpinning pH responsiveness, including dynamic covalent bonds (e.g., acylhydrazone, imine, orthoester, and borate ester), metal-ligand coordination bonds, and pH-dependent noncovalent interactions. These principles are then translated into a variety of nanocarrier platforms, such as polymeric micelles, liposomes, hydrogels, metal-organic frameworks (MOFs), PROTAC conjugates, and self-assembling peptides, all of which are designed to undergo structural or functional changes in response to acidic conditions. The convergence of these smart materials with advanced imaging modalities has enabled transformative applications, including activatable probes for high-contrast functional imaging, multistimuli responsive theranostics, organelle-precision targeting, and spatiotemporally programmed release systems. These innovations collectively enhance diagnostic accuracy, therapeutic specificity, and the potential for real-time treatment monitoring. However, clinical translation remains challenged by issues related to reproducible synthesis, long-term biocompatibility, and the complex heterogeneity of in vivo environments. Future advancements are anticipated to focus on the integration of artificial intelligence for material design, the development of closed-loop feedback systems, and rigorous translational studies to bridge the gap between laboratory innovation and clinical application.