Bioresponsive prodrug nanogel-based polycondensate strategy deepens tumor penetration and potentiates oxidative stress

• A bioresponsive DPH prodrug nanogels were synthesized by conjugating purpurin 18 with 10-hydroxycamplothecin. • The high glutathione will be consumed, and ROS can be generated after laser irradiation. • Excess ROS damages the mitochondria, thus exhibit low Δψm, exerting long-term oxidative stress. • The DPH nanogel showed an enhanced chemo-photodynamic therapy with real-time MR/NIRF dual-modal imaging. Currently single photosensitizers or chemotherapeutics implemented in clinic present huge challenges in terms of non-selective toxicity, physiological instability and unfavorable therapeutic efficacy. Herein, we designed a versatile polycondensate-based strategy for the preparation of redox-responsive prodrug nanogels (NGs) for enhanced synergistic cancer therapy. Concretely, based on a reductive cross-linking of purpurin 18 (P18) and 10-hydroxycamplothecin (HCPT), a well-designed prodrug nanogel (denoted as DPH NGs) with suitable size (~67 nm) was fabricated, which exhibited high drug loading, controlled drug release and deepened tumor penetration. The high concentration of glutathione (GSH) in the tumor microenvironment (TME) is capable of being consumed by dense disulfide bonds in DPH NGs, promoting the generation of reactive oxygen species (ROS) after irradiation at 660 nm, thus reshape the TME to reinforce photodynamic therapy against malignancies. In addition, P18 can be served as a powerful NIR fluorescence (NIRF)/ magnetic resonance (MR) imaging ability. Pleasantly, DPH NGs showed amplified oxidative stress in tumor cells to achieve an enhanced chemo-photodynamic therapy with the real-time MR/NIRF dual-modal imaging. Our findings in this study may blow up a storm for devising a simple and versatile strategies for multi-drug delivery and combined cancer therapy.