Advances in pH-responsive nanomaterials for the diagnosis and therapy of gastrointestinal diseases

Objective Gastrointestinal diseases (GIDs) pose significant challenges due to poor drug bioavailability and lack of specificity. Leveraging the unique physiological and pathological pH gradients of the GI tract, pH-responsive nanomaterials (NMs) have emerged as intelligent platforms. This review systematically evaluates the design, applications, and clinical translation barriers of pH-responsive NMs for GIDs. Methods Following PRISMA guidelines, PubMed, Web of Science, and Scopus were searched from January 2019 to March 2026 for English-language original studies. Two reviewers independently screened records, extracted data, and qualitatively assessed bias. A narrative synthesis was performed due to significant heterogeneity. Results From 857 initial records, 179 studies were included. Risk of bias assessment indicated that while most studies demonstrated clear in vitro pH-responsiveness, validation in complex in vivo environments was less consistent, and long-term safety controls were often inadequate. Mechanistically, protonation/deprotonation (reversible, adaptive) and acid-labile bond cleavage (irreversible, threshold-dependent) show distinct response kinetics. Architecturally, organic systems utilizing macro-pH gradients show higher immediate clinical potential than inorganic hybrids. Theranostically, these NMs significantly enhance imaging specificity and enable targeted therapies for inflammation, tumors, and infections. However, core translation barriers include pH microenvironment heterogeneity, mucus barriers, safety risks, and manufacturing challenges. The certainty of evidence was deemed low to very low, primarily due to the preclinical nature of the studies and high heterogeneity. Conclusions pH-responsive NMs offer promising GI targeting strategies. Overcoming physiological and manufacturing hurdles via multi-synergistic systems and rigorous safety evaluation is essential for clinical translation.