Design and application of proton gradient-based pH-responsive nanomaterials in the tumor microenvironment

The pH of the tumor microenvironment (TME) is a fundamental physicochemical parameter, and pH-responsive nanoparticles for the TME generally rely on two mechanisms: (1) protonation-induced ionization of functional groups and (2) cleavage of acid-labile chemical bonds. Based on these principles, a wide range of pH-responsive drug-delivery nanoplatforms have been developed, including inorganic nanoparticles, lipid-based nanoparticles (LNPs), polymeric micelles, metal-organic frameworks (MOFs), and protein/peptide-based nanoparticles. This review summarizes the recent progress in the design of traditional pH-responsive nanomaterials, emphasizing the molecular strategies employed in mesoporous silica nanoparticles (MSNs), liposomes, LNPs, polymeric micelles, MOFs, and protein/peptide-based nanoparticles. However, current pH-responsive nanoparticles still suffer from limited tumor selectivity, poorly defined thresholds and overreliance on simplified subcutaneous tumor models. It's necessary for comprehensive studies on pH-responsive nanoparticles, particularly using orthotopic tumor models to mimick the tumor microenvironment. Traditional pH responsiveness is largely passive, responding to acidic environments. Future developments may exploit the proton gradients not only as triggers but also as energy sources to actively drive nanoparticle targeting, providing a new paradigm for pH-based tumor nanomedicine.