Biodegradable polyphosphazene-based nanodrug to regulate redox homeostasis for augmented chemo-photodynamic therapy

Photodynamic therapy (PDT) is more precise than traditional tumor therapy. Nevertheless, PDT efficiency often is hindered by the antioxidant defense system which deplete the required reactive oxide species (ROS). Here we developed a simple but universal method by assembling anticancer drug (resveratrol, RV), photosensitizer (methylene blue, MB) and glutathione (GSH)-sensitive molecules (bis-(4-hydroxyphenyl)-disulfide, HPS) to covalent linking with hexachlorocyclotriphosphazene (HCCP) onto the Fe 3 O 4 to construct a versatile drug delivery nanosystem (FHRHM). Notably, as a multifunctional nanodrug it shows good physiological stability, biocompatibility, and pH/GSH-responsive property to realize the RV and MB controlled release in tumor microenvironment (TME), maximum magnetic resonance (MR)/fluorescence (FL) imaging guided for synergistic chemo-photodynamic therapy (CT-PDT). Especially, the cross-linked FHRHM could be decomposed via reacting with high level of GSH to accelerate release MB for exogenous ROS generation, as well as disrupted disulfide bond (-S-S-) of HPS through depleting GSH to further reduce the endogenous ROS scavenging in TME, thus double amplifying the PDT and simultaneously enhancing CT to induce Hela cells death. This work highlights a novel strategy to construct TME-dissociable nanodrug for augmented CT-PDT via regulation of redox homeostasis, may provide a promising translational approach for tumor theranostics.