The conventional inorganic semiconductors are not suitable for in vivo therapeutic nanomedicine because of the lack of an adequate and safe irradiation source to activate them. This work reports on the rational design of titania (TiO)-based semiconductors for enhanced and synergistic sono-/photoinduced tumor eradication by creating an oxygen-deficient TiO layer onto the surface of TiO nanocrystals, which can create a crystalline-disordered core/shell structure (TiO@TiO) with black color. As found in the lessons from traditional photocatalysis, such an oxygen-deficient TiO layer with abundant oxygen defects facilitates and enhances the separation of electrons (e) and holes (h) from the energy-band structure upon external ultrasound irradiation, which can significantly improve the efficacy of sono-triggered sonocatalytic tumor therapy. Such an oxygen-deficient TiO layer can also endow black titania nanoparticles with high photothermal-conversion efficiency (39.8%) at the NIR-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Both in vitro cell level and systematic in vivo tumor-bearing mice xenograft evaluations have demonstrated the high synergistic efficacy of combined and enhanced sonodynamic therapy and photothermal ablation as assisted by oxygen-deficient black titania, which has achieved complete tumor eradication with high therapeutic biosafety and without obvious reoccurrence. This work not only provides the paradigm of high therapeutic efficacy of a combined sono-/photoinduced tumor-treatment protocol but also significantly broadens the nanomedical applications of semiconductor-based nanoplatforms by rational design of their nanostructures and control of their physiochemical properties.

Two-dimensional (2D) MXenes have emerged as a promising planar theranostic nanoplatform for versatile biomedical applications; but their in vivo behavior and performance has been severely influenced and hindered by a lack of necessary surface chemistry for adequate surface engineering. To solve this critical issue, this work employs versatile sol-gel chemistry for the construction of a unique “therapeutic mesopore” layer onto the surface of 2D niobium carbide (Nb2C) MXene.Methods: The in situ self-assembled mesopore-making agent (cetanecyltrimethylammonium chloride, in this case) was kept within the mesopores for efficient chemotherapy. The abundant surface saline chemistry of mesoporous silica-coated Nb2C MXene was further adopted for stepwise surface engineering including PEGylation and conjugation with cyclic arginine-glycine-aspartic pentapeptide c(RGDyC) for targeted tumor accumulation.Results: 2D Nb2C MXenes were chosen based on their photothermal conversion capability (28.6%) in the near infrared (NIR)-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Systematic in vitro and in vivo assessments demonstrate targeted and enhanced chemotherapy and photothermal hyperthermia of cancer (U87 cancer cell line and corresponding tumor xenograft; inhibition efficiency: 92.37%) in the NIR-II biowindow by these mesopore-coated 2D Nb2C MXenes.Conclusion: This work not only significantly broadens the biomedical applications of 2D Nb2C MXene for enhanced cancer therapy, but also provides an efficient strategy for surface engineering of 2D MXenes to satisfy versatile application requirements.

Despite the merits of high tissue-penetrating depth, no ionizing radiation, and low cost, sonodynamic therapy (SDT) still suffers from a low quantum yield of reactive oxygen species (ROS), limited delivery efficiency, and potential toxicity of sonosensitizers. Different from the direct delivery of sonosensitizers into tumor tissue for SDT, this work reports the fabrication of two-dimensional (2D) nanosonosensitizers/nanocatalysts (Ti3C2/CuO2@BSA) for the in situ generation of nanosonosensitizers by responding to the tumor microenvironment, achieving the high-performance and synergistic sonodynamic/chemodynamic tumor therapy. CuO2 nanoparticle integration on 2D Ti3C2 MXene achieved in situ H2O2 generation in an acidic tumor microenvironment for oxidizing Ti3C2 to produce TiO2 nanosonosensitizers, accompanied by the enhanced separation of electrons (e–) and holes (h+) by the carbon matrix after oxidation, further augmenting the SDT efficacy. Ultrasound irradiation during the sonodynamic process also enhanced the Cu-initiated Fenton-like reaction to produce more ROS for synergizing the sonodynamic tumor therapy. The experimental results confirm and demonstrate the synergistic therapeutic effects of chemodynamic and sonodynamic nanotherapy both in vitro and in vivo. The antitumor mechanisms of synergistic chemodynamic and sonodynamic therapies are associated with the upregulation of oxidative phosphorylation, ROS generation, and apoptosis as demonstrated by RNA sequencing. This work thus provides a distinct paradigm of 2D MXene-originated in situ nanosonosensitizer generation for augmented and synergistic sonodynamic tumor nanotherapy.

This review summarizes and discusses the construction of iron-free Fenton nanocatalysts for versatile biomedical applications. The facing challenges and future developments of these iron-free Fenton nanocatalysts for clinical translation are also outlooked.