Breaking barriers with pH-responsive nanocarriers: a new frontier in precision oncology

Cancer remains a leading cause of global mortality, underscoring the urgent need for more effective and targeted therapies. Conventional treatments such as chemotherapy and radiotherapy, while critical, are often limited by systemic toxicity, poor selectivity, and the emergence of multi-drug resistance. Nanotechnology has revolutionized cancer therapy by enabling targeted drug delivery and controlled release. Among these innovations, pH-responsive nanocarriers offer a promising strategy to exploit the acidic tumor microenvironment for site-specific drug release. This review provides a comprehensive analysis of various pH-responsive nanodelivery systems, including polymeric nanoparticles, micelles, liposomes, nanostructured lipid carriers, dendrimers, solid lipid nanoparticles, and nanoemulsions, highlighting their mechanisms, materials, and therapeutic advantages. We discuss recent advances in stimuli-responsive design, active and passive targeting approaches, and dual/multi-responsive systems that further enhance selectivity and therapeutic efficacy. Special emphasis is placed on the molecular mechanisms driving pH sensitivity, including protonation-induced charge shifts, acid-labile bond cleavage, and disruption of hydrophobic interactions. By summarizing emerging preclinical findings and clinical prospects, this review underscores the critical role of pH-responsive nanocarriers in advancing targeted cancer therapy while addressing key challenges such as stability, immune evasion, and drug release control. Future directions for clinical translation are also outlined, positioning pH-sensitive systems as a pivotal innovation in oncological nanomedicine.