Acid-Responsive Drug Delivery Systems: Advances andPerspectives

Abstract Acid-responsive drug delivery systems have evolved into versatile platforms for achieving spatially and temporally controlled drug activation by exploiting pathological and intracellular acidity. Despite significant advances in prodrug- and carrier-based systems, key challenges remain, including pH heterogeneity, limited understanding of structure–property–function relationships, and translational barriers. Future efforts will focus on developing ultra-sensitive and programmable systems with precisely tunable response thresholds. The integration of multi-stimuli responsiveness, logic-gated release mechanisms, and immunomodulatory functions is expected to enhance targeting specificity and therapeutic efficacy. In addition, improving biological barrier penetration and intracellular delivery remains critical, particularly for macromolecular therapeutics. Simplified, scalable designs with well-defined structures will be essential for clinical translation. Overall, acid-responsive drug delivery systems are transitioning toward intelligent, microenvironment-adaptive systems, offering significant potential for next-generation precision medicine.