On-demand manipulation of tumorigenic microenvironments by nano-modulator for synergistic tumor therapy

Proper manipulation of tumorigenic microenvironments has been considered as one of the most effective approaches for tumor therapy, which is still a challenge to be well performed. Herein, a nano-modulator was fabricated to manipulate the hypoxia, glucose, radicals and local temperature in tumor tissue as needed, which consists of hemoglobin (Hb) and ferric ion (Fe³⁺) co-conjugated polydopamine (PDA) as core, glucose oxidase (GOD) as shell, and folic acid (FA) modified polyethylene glycol (PEG) as corona. The PEG-FA corona not only protected Hb and GOD against protease in blood circulation, but serve as tumor targeting agent for tumor specific accumulation of the nano-modulator. The Hb is in charge of oxygen supply to reverse the hypoxic environment of tumor tissue, which promotes the function of GOD to achieve rapid glucose consumption and hydrogen peroxide generation. The polydopamine was employed to raise local temperature under NIR irradiation, meanwhile to continuously reduce Fe³⁺ to produce ferrous ions (Fe²⁺), which further catalyze hydrogen peroxide to cytotoxic hydroxyl radicals via Fenton reaction. Both in vitro and in vivo results showed excellent tumor inhibition and high survival rate of tumor-bearing mice after treatment by our nano-modulator, indicating this synergistic therapy via on-demand manipulation of various tumorigenic microenvironments could be a green approach for tumor treatment with high efficiency and minimum side effects.