An injectable dual-layer chitosan-alginate nano-hydrogel incorporated Cu(I)-isopolymolybdate-based metal-organic framework tailored for three-in-one anti-cancer nanotherapy.

Designing potential agents and constructing hydrophilic nano-hydrogel platforms for biomedical and pharmaceutical applications, especially for polyoxometalate-based metal-organic frameworks (PMOF), present both great desirability and significant challenges. A unique open porous Cu(I)-isopolymolybdate-based metal-organic framework (CCUT) has been self-assembled through ionothermal processes for in vivo synergistic anti-cancer therapy. The periodicity of Drugs@CCUT-1 (nano-crystals of CCUT after cation exchange and anti-cancer drugs upload) has been investigated by synchrotron wide-angle X-ray scattering, confirming the lattice structure unchanged. To mitigate toxicity, enhance stimuli-responsive drug delivery, hydrophilicity, and biocompatibility, an injectable dual-layer chitosan//alginate-based nano-hydrogel is developed to incorporate Drugs@CCUT-1. Potential interactions between the chitosan layer and the surface of CCUT-1 have been analyzed by Density Functional Theory (DFT). Furthermore, the nanoparticles Drugs@CCUT-1@Gel exhibit efficient type I photodynamic therapy (PDT) and chemodynamic therapy (CDT) within the bio-window, effectively eradicating tumors in deep tissue. CCUT-1 generates a substantial amount of reactive oxygen species (ROS), stimulating the Keap1-Nrf2 signaling pathway and resulting in the expression of phase II enzymes, typically HO-1. CCUT-1@Gel not only demonstrates high capacity for anti-cancer drug upload and release, but also exhibits strong synergistic CDT/PDT in vivo anti-tumor efficacy. Hence, CCUT-1@Gel represents a promising in vivo nano-platform for synergistic chemotherapy (CT)/CDT/PDT three-in-one anti-cancer approach.