A Multifunctional Cascade Bioreactor Based on Hollow-Structured Cu₂ MoS₄ for Synergetic Cancer Chemo-Dynamic Therapy/Starvation Therapy/Phototherapy/Immunotherapy with Remarkably Enhanced Efficacy.

Abstract

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu₂ MoS₄ (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo-dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu^1+/2+ , Mo^4+/6+ ) exhibit Fenton-like, glutathione (GSH) peroxidase-like and catalase-like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton-like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase-like CMS could react with endogenous H₂ O₂ to generate O₂ for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H₂ O₂ . The regenerated H₂ O₂ can devote to Fenton-like reaction for realizing GOx-catalysis-enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor-killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O₂ ^- ) generation performance. More importantly, the PEGylated CMS@GOx-based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.