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a b s t r a c t a r t i c l e i n f oThe dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. Cancer treatments using a single therapeutic agent often result in limited clinical outcomes due to tumor heterogeneity and drug resistance. Combination therapies using multiple therapeutic modalities can synergistically elevate anti-cancer activity while lowering doses of each agent, hence, reducing side effects. Co-administration of multiple therapeutic agents requires a delivery platform that can normalize pharmacokinetics and pharmacodynamics of the agents, prolong circulation, selectively accumulate, specifically bind to the target, and enable controlled release in target site. Nanomaterials, such as polymeric nanoparticles, gold nanoparticles/cages/shells, and carbon nanomaterials, have the desired properties, and they can mediate therapeutic effects different from those generated by small molecule drugs (e.g., gene therapy, photothermal therapy, photodynamic therapy, and radiotherapy). This review aims to provide an overview of developing multi-modal therapies using nanomaterials ("combo" nanomedicine) along with the rationale, up-to-date progress, further considerations, and the crucial roles of interdisciplinary approaches.

Photodynamic therapy (PDT) is an emerging, non-invasive therapeutic strategy that involves photosensitizer (PS) drugs and external light for the treatment of diseases. Despite the great progress in PS-mediated PDT, their clinical applications are still hampered by poor water solubility and tissue/cell specificity of conventional PS drugs. Therefore, great efforts have been made towards the development of nanomaterials that can tackle fundamental challenges in conventional PS drug–mediated PDT for cancer treatment. This review highlights recent advances in the development of nano-platforms, in which various functionalized organic and inorganic nanomaterials are integrated with PS drugs, for significantly enhanced efficacy and tumor-selectivity of PDT.

RNA interference (RNAi) has been regarded as a revolutionary tool for manipulating target biological processes as well as an emerging and promising therapeutic strategy. In contrast to the tangible and obvious effectiveness of RNAi in vitro, silencing target gene expression in vivo using small interfering RNA (siRNA) has been a very challenging task due to multiscale barriers, including rapid excretion, low stability in blood serum, nonspecific accumulation in tissues, poor cellular uptake and inefficient intracellular release. This minireview introduces major challenges in achieving efficient siRNA delivery in vivo and discusses recent advances in overcoming them using chemically modified siRNA, viral siRNA vectors and nonviral siRNA carriers. Enhanced specificity and efficiency of RNAi in vivo via selective accumulations in desired tissues, specific binding to target cells and facilitated intracellular trafficking are also commonly attempted utilizing targeting moieties, cell‐penetrating peptides, fusogenic peptides and stimuli‐responsive polymers. Overall, the crucial roles of the interdisciplinary approaches to optimizing RNAi in vivo, by efficiently and specifically delivering siRNA to target tissues and cells, are highlighted.

The high intracellular oxidative stress in a cancer cell is a biologically relevant stimulus for efficient intracellular delivery of therapeutic genes. In this study, reactive oxygen species (ROS)-responsive poly(amino thioketal) (PATK) was synthesized to achieve efficient and safe intracellular gene delivery in prostate cancer cells. The DNA/PATK polyplexes were efficiently disassembled upon exposure to high levels of ROS in prostate cancer cells, leading to enhanced intracellular release of DNA in the cells. As a result, DNA/PATK polyplexes showed significantly higher gene transfection efficiency than their non-degradable counterparts did. In addition, conjugation of GRP78 protein-targeting peptide to the PATK not only increased its cellular uptake in prostate cancer cells but also enhanced gene transfection efficiency. This study demonstrates that ROS-responsive PATK functionalized with a cancer-targeting peptide is a promising gene carrier for safe, efficient, and cancer-targeted gene delivery.