Reactive oxygen species (ROS) play crucial roles in biological metabolism and intercellular signaling. However, ROS level is dramatically elevated due to abnormal metabolism during multiple pathologies, including neurodegenerative diseases, diabetes, cancer, and premature aging. By taking advantage of the discrepancy of ROS levels between normal and diseased tissues, a variety of ROS-sensitive moieties or linkers have been developed to design ROS-responsive systems for the site-specific delivery of drugs and genes. In this review, we summarized the ROS-responsive chemical structures, mechanisms, and delivery systems, focusing on their current advances for precise drug/gene delivery. In particular, ROS-responsive nanocarriers, prodrugs, and supramolecular hydrogels are summarized in terms of their application for drug/gene delivery, and common strategies to elevate or diminish cellular ROS concentrations, as well as the recent development of ROS-related imaging probes were also discussed.

Efficient intracellular delivery of protein drugs and tumor-specific activation of protein functions are critical toward anti-cancer protein therapy. However, an omnipotent protein delivery system that can harmonize the complicated systemic barriers as well as spatiotemporally manipulate protein function is lacking. Herein, an "all-functions-in-one" nanocarrier doped with photosensitizer (PS) is developed and coupled with reactive oxygen species (ROS)-responsive, reversible protein engineering to realize cancer-targeted protein delivery, and spatiotemporal manipulation of protein activities using long-wavelength visible light (635 nm) at low power density (5 mW cm −2 ). Particularly, RNase A is caged with H 2 O 2 -cleavable phenylboronic acid to form 4-nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonate (NBC)-modified RNase (RNBC), which is encapsulated in aciddegradable, ketal-crosslinked PEI (KPEI)-based nanocomplexes (NCs) coatedwith PS-modified hyaluronic acid (HA). Such NCs harmonize the critical processes for protein delivery, wherein HA coating renders NCs with long blood circulation and cancer cell targeting, and KPEI enables endosomal escape as well as acid-triggered intracellular RNBC release. Tumor-specific light irradiation generates H 2 O 2 to kill cancer cells and restore the protein activity, thus achieving synergistic anti-cancer efficacy. It is the first time to photomanipulate protein functions by coupling ROS-cleavable protein caging with PS-mediated ROS generation, and the "all-functions-in-one" nanocarrier represents a promising example for the programmed anti-cancer protein delivery.

Light as an external stimulus can be precisely manipulated in terms of irradiation time, site, wavelength, and density. As such, photoresponsive drug/gene delivery systems have been increasingly pursued and utilized for the spatiotemporal control of drug/gene delivery to enhance their therapeutic efficacy and safety. In this review, we summarized the recent research progress on photoresponsive drug/gene delivery, and two major categories of delivery systems were discussed. The first category is the direct responsive systems that experience photoreactions on the vehicle or drug themselves, and different materials as well as chemical structures responsive to UV, visible, and NIR light are summarized. The second category is the indirect responsive systems that require a light-generated mediator signal, such as heat, ROS, hypoxia, and gas molecules, to cascadingly trigger the structural transformation. The future outlook and challenges are also discussed at the end.

The precise and selective delivery of chemodrugs into tumors represents a critical requirement for anti-cancer therapy. Intelligent delivery systems that are responsive to a single internal or external stimulus often lack sufficient cancer selectivity, which compromises the drug efficacy and induces undesired side effects. To overcome this dilemma, we herein report a cancer-targeting vehicle which allows highly cancer-selective drug release in response to cascaded external (light) and internal (hypoxia) dual triggers. In particular, doxorubicin (DOX)-loaded, hypoxia-dissociable nanoparticles (NPs) were prepared from self-assembled polyethylenimine-nitroimidazole (PEI-NI) micelles that were further co-assembled with hyaluronic acid-Ce6 (HC). Upon accumulation in tumor cells, tumor site-specific light irradiation (660 nm, 10 mW cm) generated high levels of reactive oxygen species (ROS) and greatly enhanced the hypoxic levels to induce NP dissociation and accordingly DOX release. A synergistic anti-cancer efficacy between DOX-mediated chemotherapy and Ce6-mediated photodynamic therapy (PDT) was thus achieved, resulting in reduced side effects to normal tissues/cells. This study therefore provides an effective method to control the cancer-specific drug delivery by responding to cascaded multiple triggers, and it renders promising applications for the programmed combination of chemotherapy and PDT toward cancer treatment.