Pathogenic bacterial infection and the presence of drug-resistant bacteria have been threatening the health of human. Phototherapy has attracted increasing attention for treating tissue infections because it is noninvasive and does not lead to drug resistance. Herein, we construct a Cu co-coordinated donor-acceptor type (D-A) covalent organic framework-like (COF-like) and sodium alginate (SA) hydrogel (CTCS hydrogel) with photocatalytic and anti-inflammatory properties for the treatment of wound infection. The COF-like (TCPP-Cur) can be photoexcited with 660 nm light to produce electron-hole pairs that would be separated by donor-acceptor pairs. The co-coordinated Cu can reduce the band gap of TCPP-Cur, increase the separation rate of photogenerated electron-hole pairs, and improve the photocatalytic performance of CTCS hydrogel. Under 660 nm irradiation, the CTCS hydrogel can achieve 99.95% and 98.5% bactericidal activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) within 20 min owing to the synergistic interactions of the photothermal and photocatalytic effects. In vivo tests have shown that CTCS hydrogel can reduce the expression of TNF-α and enhance the expression of IL-10 and VEGF to promote wound healing and tissue regeneration. This photocatalytic hydrogel provides a promising strategy for reconstructing bacterially infected tissues rapidly. 

In situ fabrication of co-coordinated TCPP-Cur donor-acceptor-type covalent organic framework-like photocatalytic hydrogel for rapid therapy of bacteria-infected wounds

Evoking robust immunogenic cell death by synergistic sonodynamic therapy and glucose depletion using Au clusters/single atoms modified TiO2 nanosheets

The chemotherapy efficacy of nanodrugs is restricted by poor tumor targeting and uptake. Here, an engineered biohybrid living material (designated as EcN@HPB) is constructed by integrating paclitaxel and BAY-876 bound human serum albumin nanodrugs (HPB) with Escherichia coli Nissle 1917 (EcN). Due to the inherent tumor tropism of EcN, EcN@HPB could actively target the tumor site and competitively deprive glucose through bacterial respiration. Thus, albumin would be used as an alternative nutrient source for tumor metabolism, which significantly promotes the internalization of HPB by tumor cells. Subsequently, BAY-876 internalized along with HPB nanodrugs would further depress glucose uptake of tumor cells via inhibiting glucose transporter 1 (GLUT1). Together, the decline of glucose bioavailability of tumor cells would activate and promote the macropinocytosis in an AMP-activated protein kinase (AMPK)-dependent manner, resulting in more uptake of HPB by tumor cells and boosting the therapeutic outcome of paclitaxel.

Interference of Glucose Bioavailability of Tumor by Engineered Biohybrids for Potentiating Targeting and Uptake of Antitumor Nanodrugs.

Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O2 supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy.A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named tLyP-1H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H2O2, which in coordination with 1O2 produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O2 from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O2 supply in vitro, and achieve significant tumor inhibition in vivo.We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O2 supply, which ultimately synergistically enhanced cascade therapy. 

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Tumor-penetrating nanoplatform with ultrasound “unlocking” for cascade synergistic therapy and visual feedback under hypoxia

Energy band structure of inorganic nano-sonosensitizers is usually optimized by surface decoration with noble metals or metal oxide semiconductors, aiming to enhance interfacial charge transfer, augment spin-flip and promote radical generation. To avoid potential biohazards of metallic elements, herein, metal-free graphitic carbon nitride quantum dots (g-C3 N4 QDs) are anchored onto hollow mesoporous TiO2 nanostructure to formulate TiO2 @g-C3 N4 heterojunction. The direct Z-scheme charge transfer significantly improves the separation/recombination dynamics of electron/hole (e- /h+ ) pairs upon ultrasound (US) stimulation, which promotes the yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH). The conjugated g-C3 N4 QDs with peroxidase-mimic activity further react with the elevated endogenous H2 O2 and aggravate oxidative stress. After loading prodrug romidepsin (RMD) in TiO2 @g-C3 N4 , stimulus-responsive drug delivery can be realized by US irradiation. The disulfide bridge of the released RMD tends to be reduced by glutathione (GSH) into a monocyclic dithiol, which arrests cell cycle in G2/M phase and evokes apoptosis through enhanced histone acetylation. Importantly, reactive oxygen species accumulation accompanied by GSH depletion is devoted to deleterious redox dyshomeostasis, leading to augmented systemic oncotherapy by eliciting antitumor immunity. Collectively, this paradigm provides useful insights in optimizing the performance of TiO2 -based nano-sonosensitizers for tackling critical diseases.

Ultrasound-Activatable g-C3 N4 -Anchored Titania Heterojunction as an Intracellular Redox Homeostasis Perturbator for Augmented Oncotherapy.

To date, the construction of heterogeneous interfaces between sonosensitizers and other semiconductors or noble metals has aroused increasing attention, owing to an enhanced interface charge transfer, augmented spin-flip, and attenuated activation energy of oxygen. Here, a smart therapeutic nanoplatform is constructed by surface immobilization of glucose oxidase (GOx) onto a TiO2@Pt Schottky junction. The sonodynamic therapy (SDT) and starvation therapy (ST) mediated by TiO2@Pt/GOx (TPG) promote systemic tumor suppression upon hypoxia alleviation in tumor microenvironment. The band gap of TiO2@Pt is outstandingly decreased to 2.9 eV, in contrast to that of pristine TiO2. The energy structure optimization enables a more rapid generation of singlet oxygen (1O2) and hydroxyl radicals (•OH) by TiO2@Pt under ultrasound irradiation, resulting from an enhanced separation of hole-electron pair for redox utilization. The tumorous reactive oxygen species (ROS) accumulation and GOx-mediated glucose depletion facilitate oxidative damage and energy exhaustion of cancer cells, both of which can be tremendously amplified by Pt-catalyzed oxygen self-supply. Importantly, the combinatorial therapy triggers intense immunogenetic cell death, which favors a follow-up suppression of distant tumor and metastasis by evoking antitumor immunity. Collectively, this proof-of-concept paradigm provides an insightful strategy for highly efficient SDT/ST, which possesses good clinical potential for tackling cancer.

Platinum-Titania Schottky Junction as Nanosonosensitizer, Glucose Scavenger, and Tumor Microenvironment-Modulator for Promoted Cancer Treatment.

The therapeutic exploration of nano-zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano-sonosensitizer of ZrO2- x @Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen-deficient ZrO2- x . Compared to 3.09 eV of nano-ZrO2- x , the bandgap of ZrO2- x @Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e- /h+ separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase-mimic activity can promote 1 O2  generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), US-stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals (• R). US-triggered reactive oxygen species generation and hyperthermia-induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic-thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof-of-concept paradigm expands the medical use of nano-zirconia and provides useful insights for its therapeutic perspectives.

Yinmin Zhao

Papers

Platinum-Titania Schottky Junction as Nanosonosensitizer, Glucose Scavenger, and Tumor Microenvironment-Modulator for Promoted Cancer Treatment.

Ultrasound-Activatable g-C3 N4 -Anchored Titania Heterojunction as an Intracellular Redox Homeostasis Perturbator for Augmented Oncotherapy.

Zirconia-Platinum Nanohybrids for Ultrasound-Activated Sonodynamic-Thermodynamic Bimodal Therapy by Inducing Intense Intracellular Oxidative Stress.