Bioresponsive Nanoparticles Boost Starvation Therapy and Prevent Premetastatic Niche Formation for Pulmonary Metastasis Treatment.

In the process of tumor metastasis, tumor cells can acquire invasion by excessive uptake of nutrients and energy and interact with the host microenvironment to shape a premetastatic niche (PMN) that facilitates their colonization and progression in the distal sites. Pyruvate is an essential nutrient that engages in both energy metabolism and remodeling of the extracellular matrix (ECM) in the lungs for PMN formation, thus providing a target for tumor metastasis treatment. There is a paucity of strategies focusing on PMN prevention, which is key to metastasis inhibition. Here, we design a bioresponsive nanoparticle (HP/GU) based on a disulfide-cross-linked hyperbranched polyethylenimine (D-PEI) core and a hyaluronic acid (HA) shell with a reactive oxygen species (ROS)-sensitive cross-linker between them to encapsulate glucose oxidase (GOX) and a mitochondrial pyruvate carrier (MPC) inhibitor via electrostatic interaction, which reinforces starvation therapy and reduces PMN formation in the lungs via inhibiting pyruvate metabolism. In tumor cells, GOX and MPC inhibitors can be rapidly released and synergistically reduce the energy supply of tumor cells by consuming glucose and inhibiting pyruvate uptake to decrease tumor cell invasion. MPC inhibitors can also reduce ECM remodeling by blocking cellular pyruvate metabolism to prevent PMN formation. Consequently, HP/GU achieves an efficient inhibition of both primary and metastatic tumors and provides an innovative strategy for the treatment of tumor metastases.

A Visible Light-Responsive TiO2 Photocathode Achieved by a Rh Dopant.

Developing an efficient and stable photocathode material for photoelectrochemical solar water splitting remains challenging. Herein, we demonstrate the potential of rutile TiO2 as a photocathode by Rh doping with visible light absorption up to 640 nm and an onset potential of 0.9 V versus the reversible hydrogen electrode. The dopant transforms the rutile host from an n-type semiconductor to a p-type one, as confirmed by the Mott-Schottky curve and kelvin probe force microscopy. Physical and photoelectrochemical analyses further suggest that the doping mechanism is dependent on concentration. Lower levels of dopants generate localized Rh3+, while higher levels favor Rh4+ that interacts more strongly with the O 2p orbitals. The latter is found not only to extend the visible light absorption range but also to facilitate charge transport. This work elucidates the role of the Rh dopant in adjusting the photoelectrochemical behavior of TiO2, and it provides a promising photocathode material for solar energy conversion.

ROS-responsive core-shell nano-inhibitor impedes pyruvate metabolism for reinforced photodynamic therapy and interrupted pre-metastatic niche formation.

The formation of pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor requires the communication between the tumor cells and the host environment. Pyruvate is a fundamental nutrient by which the tumor cells metabolically reshape the extracellular matrix in the lung to facilitate their own metastatic development. Here we report a combination regimen by integrating the photo-sensitizer and the mitochondrial pyruvate carrier (MPC) inhibitor in a dendritic polycarbonate core-hyaluronic acid shell nano-platform with multivalent reversible crosslinker embedded in it (DOH-NI+L) to reinforce photodynamic therapy (PDT) toward the primary tumor and interrupt PMN formation in the lung via impeding pyruvate uptake. We show that DOH-NI+L mediates tumor-specific MPC inhibitor liberation, inhibiting the aerobic respiration for facilitated PDT and restraining ATP generation for paralyzing cell invasion. Remarkably, DOH-NI+L is demonstrated to block the metabolic crosstalk of tumor cell-host environment by dampening pyruvate metabolism, provoking a series of metabolic responses and resulting in the pulmonary PMN interruption. Consequently, DOH-NI+L realizes a significant primary tumor inhibition and an efficient pulmonary metastasis prevention. Our research extends nano-based anti-metastatic strategies aiming at PMN intervention and such a dendritic core-shell nano-inhibitor provides an innovative paradigm to inhibit tumor growth and prevent metastasis efficiently. STATEMENT OF SIGNIFICANCE: In the progression of cancer metastasis, the formation of a pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor is one of the rate-limiting stages. The current nano-based anti-metastatic modalities mainly focus on targeted killing of tumor cells and specific inhibition of tumor cell invasion, while nanomedicine-mediated interruption of PMN formation has been rarely reported. Here we report a combination regimen by integrating a photo-sensitizer and an inhibitor of mitochondrial pyruvate carrier in a dendritic core-shell nano-platform with a reversible crosslinker embedded in it to reinforce PDT toward the primary tumor and interrupt PMN formation via impeding the uptake of pyruvate that is a fundamental nutrient facilitating aerobic respiration and PMN formation. Our research proposed a nano-based anti-metastatic strategy aiming at PMN intervention.

Probing Intra-Gap States Mediated Charge Dynamics of Rh-Doped Rutile TiO2 Photocatalyst by Light-Modulated Photocurrent Spectroscopies.

The intra-gap states that are introduced into a semiconducting photocatalyst via dopants and other defects have significant implications on the transport dynamics of photoexcited electrons and holes during an aqueous light-driven reaction. In this work, mechanistic understanding of Rh-doped rutile, a promising photocatalyst for hydrogen production from water, is gained by systematic assessment combining intensity-modulated photocurrent spectroscopy with sub-gap excitations and alternating-current photocurrent spectroscopy. These operando techniques not only help in discovering a new electronic transport path in Rh-rutile via surface Rh4+ species and elucidating complex interaction between electrolyte molecules and semiconductors, but also underscore the potential of utilizing multiple sub-gap excitations synergistically. This combination offers a powerful tool for acquiring insight into photo-physical and photo-chemical behaviors of photo(electro)catalysts with intra-gap states.

Insight into the Light-Driven Hydrogen Production over Pure and Rh-Doped Rutile in the Presence of Ascorbic Acid: Impact of Interfacial Chemistry on Photocatalysts.

The surface states of a semiconductor photocatalyst are essential for interfacial charge transfer in heterogeneous photocatalytic reactions. Here, we report that the light-driven hydrogen evolution reaction (HER) activity of 0.5 mol % Rh-doped rutile increases by more than 30 times compared with that of rutile when ascorbic acid is used as a sacrificial agent. Intensity-modulated photocurrent spectroscopy and surface photovoltage spectroscopy are employed to reveal the impact of surface states on the photo-oxidation reactions. It is found that the adsorption of ascorbic acid molecules dramatically reduces the activity of rutile due to coverage of the HER-active Ti sites. Nevertheless, for Rh-doped rutile, ascorbic acid neutralizes the Rh(IV) sites that would otherwise cause severe recombination of electron-hole pairs and resurrects its photocatalytic performance. This work demonstrates the key role of interfacial chemistry in photocatalytic reactions and provides a strategy for excavating the potential of various photocatalysts.