Design and Application of Proton Gradients-Based pH-Responsive Nanomaterials in the Tumor Microenvironment

Abstract

pH plays a critical role in the tumor microenvironment (TME). From a broader biological perspective, proton gradients represent one of the earliest and most fundamental energy sources utilized by living systems, and they remain essential today. pH-responsive nanoparticles designed for the TME typically 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 nanoplatforms have been developed, including inorganic nanoparticles, lipid-based nanoparticles, and polymeric micelles. Traditional pH-responsiveness is primarily passive or stimulus-triggered in nature, merely reacting to acidic environments without actively exploiting the proton gradient as a driving force for nanoparticle behavior. In this review, we summarize recent advances in the design of conventional pH-responsive nanomaterials, with a focus on the molecular strategies employed in MSNs, liposomes, LNPs, and polymeric micelles. Finally, we propose that future developments may harness proton gradients not just as triggers, but as potential sources of energy to actively drive nanoparticle targeting, offering a new paradigm for pH-based tumor nanomedicine.