Biomolecule-based stimuli-responsive nanohybrids for tumor-specific and cascade-enhanced synergistic therapy

Poor tumor specificity is one of the key obstacles for clinical applications of nanotheranostic agents, consequently leading to serious side effects and unsatisfactory therapeutic efficacy. Herein, biomolecule-based nanohybrids (named as Hb-PDA-GOx) with multiple stimuli-responsiveness were designed and fabricated to enhance tumor-specific therapy. The nanohybrids embodied two proteins, i.e., hemoglobin (Hb) and glucose oxidase (GOx), which exhibited cascade catalytic activity selectively within the tumor microenvironment (TME). Specifically, GOx catalyzes the overexpressed glucose into gluconic acid and hydrogen peroxide (H₂O₂), which not only initiated starvation therapy (ST) through cutting off the nutrition supply for carcinoma cells, but also provided H₂O₂ for sequential Fenton reaction induced by Hb that generating biotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). Moreover, localized heat generation from polydopamine (PDA) in the nanohybrids can implement photothermal therapy (PTT) and reinforce the CDT efficacy. Excitingly, effective eradication of solid tumors and significant suppression of metastatic tumors growth were achieved by utilizing Hb-PDA-GOx as a versatile theranostic agent. All these results had been verified by in vitro and/or in vivo experiments. In light of the superior anticancer effects and insignificant systemic toxicity, the as-fabricated biomolecule-based nanohybrids could be employed as a promising agent for tumor-specific therapy. More importantly, the high biocompatibility and biodegradability of the selected biomolecules would facilitate subsequent clinical translation. STATEMENT OF SIGNIFICANCE: (1) A facile one-pot synthesis strategy was proposed to fabricate biomolecule-based tumor theranostic agent with high biocompatibility and biodegradability, which would facilitate subsequent clinical translation; (2) The as-developed theranostic agent was endowed with multiple stimuli-responsiveness for achieving tumor-specific and cascade-enhanced synergistic therapy; (3) The in vivo experiments demonstrated that the as-developed theranostic agent can not only effectively eradicate solid tumors, but also significantly suppress metastatic tumors growth.