Smart pH-Responsive polymers in biomedical Applications: Nanoparticles, hydrogels, and emerging hybrid platforms

Stimuli-responsive materials have attracted considerable interest in biomedical research, particularly for their ability to undergo structural and functional changes in response to environmental cues. Among these, pH-responsive polymeric systems offer a promising platform for developing smart drug delivery strategies due to the naturally occurring pH gradients present throughout the human body and within pathological microenvironments. This review provides a comprehensive overview of the most recent advances in the field of pH-sensitive hydrogels and nanoparticles, including hybrid architectures that combine both systems to achieve synergistic functionalities. After a brief introduction to the chemical mechanisms governing pH-responsiveness, the discussion focuses on their relevance in biomedicine, supported by a detailed analysis of physiological and pathological pH heterogeneity. Selected case studies highlight the role of pH-responsive systems in key applications such as drug and gene delivery, cancer and osteoarthritis therapy, wound healing, and soft robotics. Special attention is given to nanocomposite hydrogel systems that integrate pH-sensitive nanoparticles into hydrogel matrices, thereby enhancing drug loading capacity, spatial control, and responsiveness to complex environments. Altogether, this work aims to underline the versatility and clinical potential of pH-responsive polymeric systems and to encourage further interdisciplinary research towards personalized, efficient, and minimally invasive therapeutic solutions. • PH-responsive systems react to pH changes by altering structure and key properties. • Polymeric NPs and hydrogels are leading, complementary pH-responsive delivery systems. • Advances in biomaterials led to hybrid pH-responsive systems with NPs and hydrogels. • Though blood pH stays near 7.4, local pH can vary widely from 1 to 8 in the body. • PH-responsive NPs and hydrogels are used in delivery, robotics, and healing.