A multifunctional hyaluronic acid-engineered mesoporous nanoreactor with HO/O self-sufficiency for pH-triggered endo-lysosomal escape and synergetic cancer therapy.

Monotherapy has poor accuracy and is easily restricted by tumor microenvironment (TME). Remodeling components of the TME to activate multimodal cancer therapy with high precision and efficiency is worth exploring. A multifunctional nanoreactor was fabricated by decorating chlorin e6-modified and PEGylated hyaluronic acid bearing diethylenetriamine-conjugated dihydrolipoic acid on the surface of glucose oxidase (GOx)-loaded hollow mesoporous CuS nanoparticles (labeled as GOx@HCuS@HA). This nanoreactor efficiently targets tumor sites, enhances cellular internalization, and swiftly escapes from endo-lysosomes after intravenous injection. Subsequently, GOx@HCuS@HA was activated in hyaluronidase and H + -rich TME to produce HO and gluconic acid through the oxidation of glucose, which not only blocks the energy supply of cancer cells, executing starvation treatment (ST), but also bolsters hydroxyl radicals (•OH)-based chemodynamic therapy (CDT) by Fenton-like reaction between HCuS and HO. Furthermore, reductive Cu ions could catalyze HO to produce O to alleviate the limitation of photodynamic therapy (PDT) for tumor hypoxia. Additionally, the photothermal effect of HCuS under NIR irradiation could increase the temperature of tumor tissues to perform photothermal therapy (PTT). This synergistic antitumor strategy could ultimately achieve precise tumor cell destruction and maintain excellent biosafety. Hence, this nanoreactor offer promising prospects for efficient tumor treatment.