Nanomedicine as a multimodal therapeutic paradigm against cancer: on the way forward in advancing precision therapy.

Recent years have witnessed dramatic improvements in nanotechnology-based cancer therapeutics, and it continues to evolve from the use of conventional therapies (chemotherapy, surgery, and radiotherapy) to increasingly multi-complex approaches incorporating thermal energy-based tumor ablation ( magnetic hyperthermia and photothermal therapy), dynamic therapy ( photodynamic therapy), gene therapy, sonodynamic therapy ( ultrasound), immunotherapy, and more recently real-time treatment efficacy monitoring ( theranostic MRI-sensitive nanoparticles). Unlike monotherapy, these multimodal therapies (bimodal, , a combination of two therapies, and trimodal, , a combination of more than two therapies) incorporating nanoplatforms have tremendous potential to improve the tumor tissue penetration and retention of therapeutic agents through selective active/passive targeting effects. These combinatorial therapies can correspondingly alleviate drug response against hypoxic/acidic and immunosuppressive tumor microenvironments and promote/induce tumor cell death through various multi-mechanisms such as apoptosis, autophagy, and reactive oxygen-based cytotoxicity, , ferroptosis, These multi-faced approaches such as targeting the tumor vasculature, neoangiogenic vessels, drug-resistant cancer stem cells (CSCs), preventing intra/extravasation to reduce metastatic growth, and modulation of antitumor immune responses work complementary to each other, enhancing treatment efficacy.