Next-generation dynamic and combinatorial nanotherapies for liver cancer: mechanisms, current advances and future perspectives

Liver Cancer, one of the most lethal cancers in adults, is distinguished by its aggressive invasion, distinctive tumor microenvironment (TME) and resistance to standard treatments, posing challenges. The TME and fibrotic extracellular matrix (ECM) hampers effective drug distribution; hence, new developments in therapeutics have brought creative solutions to these problems. To temporarily breach these barriers and enable targeted treatment, various dynamic therapies using stimuli such as focused Ultrasound, light, chemical reactions, mechanical stress, microwave induction and magnetic fields have demonstrated great promise in inducing localized and spatiotemporal therapeutic effects. This comprehensive review highlights the therapeutic mechanisms, including both chemical and biological effects and elucidates the therapeutic promise of emerging nanomedicine across individual modalities such as sonodynamic therapy (SDT), photodynamic therapy (PDT) and chemodynamic therapy (CDT), supported by preclinical evidence. Thereafter, promising combinatorial dynamic strategies with superior therapeutic effects are outlined. Furthermore, emerging next-generation modalities, including piezodynamic therapy (PZDT), microwave dynamic therapy (MWDT) and magnetodynamic therapy (MDT), with their therapeutic perspectives are discussed in detail. Although these strategies employing emerging nanomedicines have shown remarkable therapeutic potential for clinical translation, controlling physical stimulation and ensuring nanoparticle biocompatibility remain challenging. Continued innovations in medicine and chemistry will be essential for transforming dynamic strategies into clinically viable strategies for liver oncology.