Responsive agarose hydrogel incorporated with natural humic acid and MnO2nanoparticles for effective relief of tumor hypoxia and enhanced photo-induced tumor therapy

In spite of widespread applications of nano-photosensitizers, poor tumor penetration and severe hypoxia in the tumor microenvironment (TME) always result in an undesirable therapeutic outcome of photodynamic therapy (PDT). Herein, a biocompatible agarose-based hydrogel incorporated with sodium humate (SH), manganese oxide (MnO2) and chlorin e6 (Ce6) was synthesized as agarose@SH/MnO2/Ce6 through a "co-trapped" strategy during a sol-gel process and employed for combined photothermal therapy (PTT) and enhanced PDT. NIR-induced local hyperthermia is responsible for not only activating Ce6 release, but also triggering the catalytic decomposition of H2O2 mediated by MnO2 to relieve hypoxia. Such a hybrid hydrogel can realize deep tissue penetration through intratumoral injection, and exhibit remarkable tumor-site retention. Moreover, programmed laser irradiation led to an extremely high tumor growth inhibition rate of 93.8% in virtue of enhanced PTT/PDT. In addition, ultralow systemic toxicity caused by the hybrid hydrogel was further demonstrated in vivo. This reliable and eco-friendly hydrogel paves the way for the development of smart gel-based biomaterials, which respond to both exogenous and endogenous stimuli, towards the management of cancer and other major diseases.