Advances in the applications of stimulus-responsive nanomedicines for anti-cancer therapy

Current major cancer therapies are limited by nonspecific drug distribution and severe off-target toxicity. Nanomedicine has emerged as a promising strategy for targeted tumor drug delivery, leveraging nanoparticles' unique properties to enhance drug solubility, extend circulation, and enable imaging, while relying on the enhanced permeability and retention (EPR) effect and antibody/ligand recognition for passive and active targeting to accumulate at tumor sites. Stimulus-responsive nanomedicines are another trend accompanying both targeting strategies to address further issues of tissue penetration, cellular internalization, and drug release that are critical for the payload's therapeutic efficacy, they exploit the internal tumor microenvironment (TME)-specific features of pH, glutathione (GSH), Reactive oxygen species (ROS), Enzymes, and adenosine triphosphate (ATP) that are differential from normal tissues or externally introduced triggers of light, magnetic fields, ultrasound to release the therapeutic modality via a spatiotemporally controlled manner to overcome encountered barriers and enable optimal therapeutic efficacy. This review will summarize recent advances in the application of these stimulus-responsive nanomedicines in cancer therapy, focusing on their functions of achieving targeted release, improved tumor penetration, maximum efficacy, multidrug resistance reversal, TME modulation, and synergistic combination therapies. It also discusses current challenges and future directions for facilitating stimulus-responsive nanomedicines.